Novel precatalyst scaffolds for cross-coupling reactions, and methods of making and using same

ABSTRACT

The present invention provides novel transition-metal precatalysts that are useful in preparing active coupling catalysts. In certain embodiments, the precatalysts of the invention are air-stable and moisture-stable. The present invention further provides methods of making and using the precatalysts of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a 35 U.S.C. §371 national phase applicationfrom, and claims priority to, International Application No.PCT/US2015/054368, filed Oct. 7, 2015, and published under PCT Article21(2) in English, which claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application No. 62/061,319, filed Oct. 8, 2014, all of whichapplications are incorporated herein by reference in their entireties.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under 1122492 awarded byNational Science Foundation. The government has certain rights in theinvention.

BACKGROUND OF THE INVENTION

Transition metal-catalyzed cross-coupling has found applications indiverse areas of chemistry, such as total synthesis, materials andbioorganic chemistry. In fact, cross-coupling is one of the mostpowerful and general synthetic methods. In particular, the activepharmaceutical ingredients of drugs such as losartan((2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol),used to treat high blood pressure, and atazanavir (methyl N-[(1S)-1-{[(2S,3S)-3-hydroxy-4-[(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethyl-N′-{[4-(pyridin-2-yl)phenyl]methyll}butanehydrazido]-1-phenylbutan-2-yl]carbamoyl}-2,2-dimethylpropyl]carbamate), used to treat HIV, aresynthesized using cross-coupling.

The most effective cross-coupling catalysts utilize Pd and featuresterically demanding, electron-rich phosphine or N-heterocyclic carbene(NHC) ancillary ligands. The active species in catalysis, commonlymonoligated Pd(0), is often generated through the addition of excessligand to a Pd(0) source. However, the specialized ligands utilized inmost cross-coupling reactions are often as expensive as the Pd(0)source, and the use of excess ligand is not economically feasible.Instead, a variety of well-defined Pd(I) and Pd(II) precatalysts, whichfeature a 1:1 Pd:ligand ratio, have been developed.

There is still a need in the art for novel precatalysts, which can beefficiently converted to an active catalytic species. The presentinvention addresses and meets this need.

BRIEF SUMMARY OF THE INVENTION

The invention provides a precatalyst of formula (I), or a salt orsolvate thereof:

wherein in (I) each occurrence of M is independently a transition metal;each occurrence of X is independently a ligand; each occurrence of R isindependently selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl andsubstituted heteroaryl, with the proviso that each of the 5-memberedrings is substituted with at least one independently selected R; Z isCH, CR or N, with the proviso that 0-2 Z groups are N; or the Z groupsat the 5- and 6-positions are null and the Z groups at the 4- and7-positions are independently R; and, n is 1, 2, 3, or 4.

The invention further provides a precatalyst of formula (II), or a saltor solvate thereof:

wherein in (II) M is a transition metal; X is a ligand; each occurrenceof R is independently selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, heteroaryl and substituted heteroaryl, with the provisothat the 5-membered ring is substituted with at least one R; Z is CH, CRor N, with the proviso that 0-2 Z groups are N; or the Z groups at the5- and 6-positions are null and the Z groups at the 4- and 7-positionsare independently R; L is a monodentate or bidentate ligand; and n is 1,2, 3, or 4.

The invention further provides a method of preparing the precatalyst offormula (I). In certain embodiments, the method comprises contacting amixed alkaline/transition metal or alkaline-earth/transition metal saltwith the following ligand

in the presence of a base in an organic solvent to form a reactionmixture.

The invention further provides a method of preparing a precatalyst offormula (II). In certain embodiments, the method comprises contacting acatalyst of formula (I) with a ligand contemplated within the invention.

The invention further provides a method of promoting a reaction betweena first reagent and a second reagent. In certain embodiments, the methodcomprises contacting the first reagent and the second reagent in thepresence of at least one selected from the group consisting of (a) aprecatalyst of formula (I) and a ligand; and (b) a precatalyst offormula (II).

The invention further provides a method of promoting anaerobic oxidationof a primary or secondary alcohol. In certain embodiments, the methodcomprises contacting the primary or secondary alcohol with at least oneselected from the group consisting of (a) the precatalyst of formula (I)and a ligand; and (b) the precatalyst of formula (II).

In certain embodiments, each occurrence of M in (I) is independentlyselected from the group consisting of Pd, Ni and Pt. In otherembodiments, M in (II) is selected from the group consisting of Pd, Niand Pt. In yet other embodiments, the two occurrences of M in (I) areidentical. In yet other embodiments, the two occurrences of M in (I) arePd. In yet other embodiments, M in (II) is Pd.

In certain embodiments, the two occurrences of X in (I) are identical.In other embodiments, each of the two occurrences of X in (I) isindependently a weakly coordinating ligand. In yet other embodiments,each of the two occurrences of X in (I) is independently selected fromthe group consisting of halide, trifluoromethanesulfonate (triflate),tosylate, mesylate, tetrafluoroborate, tetraphenylborate,hexafluorophosphine, acetate, trifluoroacetate, acetonitrile,tetrahydrofuran, dichloromethane and water. In yet other embodiments,each of the two occurrences of X in (I) is an anion. In yet otherembodiments, X in (II) is selected from the group consisting of halide,trifluoromethanesulfonate (triflate), tosylate, mesylate,tetrafluoroborate, tetraphenylborate, hexafluorophosphine, acetate,trifluoroacetate, acetonitrile, tetrahydrofuran, dichloromethane andwater. In yet other embodiments, X in (II) is an anion.

In certain embodiments, the two ligands comprising 5-membered rings areidentical. In other embodiments, each of the 5-membered rings issubstituted with at least one R selected from the group consisting ofalkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, heteroaryl and substituted heteroaryl. In yet otherembodiments, each of the 5-membered rings is substituted with at leastone R selected from the group consisting of methyl, isopropyl andtent-butyl. In yet other embodiments, the 1- or 3-position of each ofthe 5-membered rings is substituted with R. In yet other embodiments,the 2-position of each of the 5-membered rings is substituted with R. Inyet other embodiments, each occurrence of Z is independently selectedfrom the group consisting of CH and CR.

In certain embodiments, the 5-membered ring is substituted with at leastone R selected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl andsubstituted heteroaryl. In yet other embodiments, the 5-membered ring issubstituted with at least one R selected from the group consisting ofmethyl, isopropyl and tent-butyl. In yet other embodiments, the 1- or3-position of the 5-membered rings is substituted with R. In yet otherembodiments, the 2-position of the 5-membered rings is substituted withR. In yet other embodiments, each occurrence of Z is independentlyselected from the group consisting of CH and CR.

In certain embodiments, L is a bidentate ligand, and X is present andcoordinates to M. In other embodiments, L is a bidentate ligand, and Xis absent or does not coordinate to M. In yet other embodiments, X is aweakly coordinating ligand. In yet other embodiments, L is selected fromthe group consisting of 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene and1,3-bis(2,6-bis-(diphenylmethyl)-4-methoxyphenyl) imidazol-2-ylidene.

In certain embodiments, L is a monodentate phosphine ligand. In otherembodiments, L is a bidentate phosphine ligand.

In certain embodiments, L is at least one selected from the groupconsisting of AmPhos (di-t-butylphosphino-4-dimethylaminobenzene),DavePhos (2-dicyclohexyl phosphino-2′-(N,N-dimethylamino)biphenyl),^(tBu)DavePhos(2-Di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl), QPhos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino) ferrocene), RuPhos(2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl), SPhos(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl), XPhos(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), ^(tBu)XPhos(2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl), ^(Me4tBu)XPhos(2-Di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl),BrettPhos(2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl),^(tBu)BrettPhos (2-(Di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl), ^(Ad)BrettPhos(2-(Diadamantylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl), Me-DalPhos(2-(Di-1-adamantylphosphino) phenylpiperidine), Mor-DalPhos(Di(1-adamantyl)-Di(1-adamantyl)-1-piperidinyl-phenylphosphine,triphenylphosphine, tri(o-tolyl) phosphine, tricyclohexylphosphine andtri(t-butyl)phosphine.

In certain embodiments, L is selected from the group consisting of1,1′-bis(diphenylphosphino)ferrocene (DPPF),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), 4,6-bis(diphenylphosphanyl)-10H-phenoxazine (NiXantPhos),1,2-bis(diphenylphosphino)ethane (dppe),1,1-bis(diphenylphosphino)methane (dppm),1,3-bis(diphenylphosphino)propane (dppp),1,4-bis(diphenylphosphino)butane (dppb),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),bis[(2-diphenylphosphino) phenyl] ether (DPEPhos),1,2-bis(dichlorophosphino) ethane, and1,2-bis(dicyclohexylphosphino)-ethane (dcpe).

In certain embodiments, the base comprises sodium carbonate. In otherembodiments, the organic solvent comprises methanol. In yet otherembodiments, the precatalyst precipitates from the reaction mixture. Inyet other embodiments, the mixed salt comprises [E]MX₂, wherein [E] isNa₂, K₂, Ca or Mg. In yet other embodiments, the mixed salt comprisesNa₂PdCl₂. In yet other embodiments, the mixed alkaline/transition metalsalt or a mixed alkaline-earth/transition metal salt is prepared bycontacting MX₂ with an alkaline or alkaline-earth salt in solution.

In certain embodiments, the ligand contemplated within the invention isan N-heterocyclic carbene.

In certain embodiments, the first reagent is an aromatic orheteroaromatic boronic acid or ester, and the second reagent is anaromatic or heteroaromatic halide, tosylate, triflate, mesylate,sulfamate or carbamate. In other embodiments, the first reagent is anaromatic or heteroaromatic amine, and the second reagent is an aromatic,heteroaromatic or vinylic halide, tosylate, triflate, mesylate,sulfamate or carbamate. In yet other embodiments, the first reagent isan aromatic or heteroaromatic zinc halide, and the second reagent is anaromatic, heteroaromatic or vinylic halide, tosylate, triflate,mesylate, sulfamate or carbamate. In yet other embodiments, the firstreagent is an aromatic or heteroaromatic magnesium halide, and thesecond reagent is an aromatic, heteroaromatic or vinylic halide,tosylate, triflate, mesylate, sulfamate or carbamate. In yet otherembodiments, the first reagent is an aromatic or heteroaromatic tinhalide, and the second reagent is an aromatic, heteroaromatic or vinylichalide, tosylate, triflate, mesylate, sulfamate or carbamate. In yetother embodiments, the first reagent is a ketone, aldehyde, imine, amideor ester, and the second reagent is an aromatic, heteroaromatic orvinylic halide, tosylate, triflate, mesylate, sulfamate or carbamate. Inyet other embodiments, the first reagent is an alcohol or thiol, and thesecond reagent is an aromatic, heteroaromatic or vinylic halide,tosylate, triflate, mesylate, sulfamate or carbamate. In yet otherembodiments, the first reagent is an aromatic or heteroaromatic silanol,siloxane or silane, and the second reagent is an aromatic,heteroaromatic or vinylic halide, tosylate, triflate, mesylate,sulfamate or carbamate.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention, there are depicted in thedrawings certain embodiments of the invention. However, the invention isnot limited to the precise arrangements and instrumentalities of theembodiments depicted in the drawings.

FIG. 1 is a set of molecular structures illustrating commerciallyavailable precatalysts with a 1:1 Pd-to-ligand ratio, includingprecatalysts (1) and (2).

FIG. 2 is a set of exemplary reaction schemes that can be performedusing the precatalysts of the invention.

FIG. 3 is a graph illustrating yields (as determined by gaschromatography, or GC) for Suzuki-Miyaura reactions catalyzed bydistinct precatalysts.

FIG. 4 is a scheme illustrating a pathway for activation of precatalystsof the type (ι₃-allyl)Pd(IPr)(C1) with KO′Pr (generated from KO^(t)Bu in^(i)PrOH). Both the rate of activation to Pd(0) (step i) andcomproportionation to Pd(I) (step ii) affect catalytic activity.

FIG. 5 is a scheme illustrating the synthesis of the indenyl precatalystscaffold and IPr supported precatalysts.

FIG. 6 is a graph of the observed rate constant vs. number ofequivalents of base for the activation of 1 in d₄-MeOH with K₂CO₃ in thepresence of 1,3-divinyl-1,1,3,3-tetramethyldisiloxane (dvds).

FIG. 7 illustrates product yields for a series of Suzuki-Miyaurareactions to generate tetra-ortho-substituted biaryl products catalyzedby 4d-IPr*OMe. ArX (0.50 mmol), ArB(OH)₂ (0.75 mmol), KOH (1.0 mmol),4d-IPr*OMe (0.5 or 1.0 mol %), THF (1.0 mL); isolated yields average oftwo runs.

FIG. 8 illustrates preparation and yields of phosphine supportedprecatalysts.

FIG. 9 illustrates yields of products for Suzuki-Miyaura reactionsinvolving 2-heterocyclic boronic acids. ArCl (1.0 mmol), ArB(OH)₂ (1.5mmol), K₂CO₃ (2.0 mmol), 4d-XPhos (1.0 mol %), MeOH (4 mL), THF (2 mL);isolated yields average of two runs.

FIG. 10 illustrates yields of products for Suzuki-Miyaura reactionsinvolving unprotected indazoles or benzimidazoles. ArCl (1.0 mmol),ArB(OH)₂ (2.0 mmol), K₂CO₃ (2.0 mmol), 4d-SPhos (2.0 mol %), 1,4-dioxane(4 mL), MeOH (2 mL); isolated yields average of two runs.

FIG. 11 illustrates yields of products for Buchwald-Hartwig reactionsinvolving secondary amines. ArCl (1.0 mmol), Amine (1.2 mmol), NaOtBu(1.2 mmol), 4d-RuPhos (0.5 mol %), RuPhos (0.5 mol %), THF (1 mL);isolated yields average of two runs. ^(a)Used 4d-XPhos. ^(b)Used ArBr.

FIG. 12 illustrates yields of products from a-arylation of aryl methylketones. ArCl (0.53 mmol), Ketone (0.5 mmol), KOtBu (1.2 mmol), 4d-XPhos(1.0 mol %), THF (4 mL), MeOH (1 mL); isolated yields average of tworuns.

FIG. 13 illustrates yields of products for Suzuki-Miyaura reactionsinvolving alkyl trifluoroboronates. ArCl (0.5 mmol), R′R″CH—BF₃K (0.75mmol), K₂CO₃ (1.5 mmol), 4d-P^(t)Bu₃ (1.0-2.0 mol %), Toluene (1.0 mL),H₂O (0.5 mL); isolated yields average of two runs.

FIGS. 14A-14D comprise exemplary ORTEPs of 4b-IPr (FIG. 14A), 4c-IPr(FIG. 14B), 4d-IPr (FIG. 14C) and 4d-BrettPhos (FIG. 14D). Ellipsoidsshown at 30% probability. ^(i)Pr groups of IPr and hydrogen atoms areomitted for clarity.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the unexpected discovery of noveltransition-metal precatalysts that are useful in preparing activecoupling catalysts. In certain embodiments, the precatalysts of theinvention are air-stable and moisture-stable. In other embodiments, theprecatalysts of the invention comprise a dimeric precatalyst of formula(I) or a monomeric precatalyst of formula (II). The present inventionfurther provides methods of making and using the precatalysts of theinvention.

Definitions

As used herein, each of the following terms has the meaning associatedwith it in this section.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in animalpharmacology, pharmaceutical science, separation science and organicchemistry are those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more thanone (i.e., to at least one) of the grammatical object of the article. Byway of example, “an element” means one element or more than one element.

As used herein, the term “about” is understood by persons of ordinaryskill in the art and varies to some extent on the context in which it isused. As used herein when referring to a measurable value such as anamount, a temporal duration, and the like, the term “about” is meant toencompass variations of ±20% or ±10%, more preferably ±5%, even morepreferably ±1%, and still more preferably ±0.1% from the specifiedvalue, as such variations are appropriate to perform the disclosedmethods.

As used herein, the term “alkenyl,” employed alone or in combinationwith other terms, means, unless otherwise stated, a stablemonounsaturated or diunsaturated straight chain or branched chainhydrocarbon group having the stated number of carbon atoms. Examplesinclude vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl,1,3-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers. Afunctional group representing an alkene is exemplified by —CH₂—CH═CH₂.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms, as defined above, connected to therest of the molecule via an oxygen atom, such as, for example, methoxy,ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs andisomers. A specific example is (C₁-C₃)alkoxy, such as, but not limitedto, ethoxy and methoxy.

As used herein, the term “alkyl,” by itself or as part of anothersubstituent means, unless otherwise stated, a straight or branched chainhydrocarbon having the number of carbon atoms designated (i.e., C₁-C₁₀means one to ten carbon atoms) and includes straight, branched chain, orcyclic substituent groups. Examples include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tent-butyl, pentyl, neopentyl, hexyl, andcyclopropylmethyl. A selected example is (C₁-C₆)alkyl, such as, but notlimited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl andcyclopropylmethyl.

As used herein, the term “alkynyl,” employed alone or in combinationwith other terms, means, unless otherwise stated, a stable straightchain or branched chain hydrocarbon group with a triple carbon-carbonbond, having the stated number of carbon atoms. Non-limiting examplesinclude ethynyl and propynyl, and the higher homologs and isomers. Theterm “propargylic” refers to a group exemplified by —CH₂—C≡CH. The term“homopropargylic” refers to a group exemplified by —CH₂CH₂—C≡CH. Theterm “substituted propargylic” refers to a group exemplified by—CR₂—C≡CR′, wherein each occurrence of R′ is independently H, alkyl,substituted alkyl, alkenyl or substituted alkenyl, with the proviso thatat least one R′ group is not hydrogen. The term “substitutedhomopropargylic” refers to a group exemplified by —CR'₂CR′₂—C≡CR′,wherein each occurrence of R′ is independently H, alkyl, substitutedalkyl, alkenyl or substituted alkenyl, with the proviso that at leastone R′ group is not hydrogen.

As used herein, the term “AmPhos” refers todi-t-butylphosphino-4-dimethylaminobenzene.

As used herein, the term “aromatic” refers to a carbocycle orheterocycle with one or more polyunsaturated rings and having aromaticcharacter, i.e. having (4n+2) delocalized π (pi) electrons, where n isan integer.

As used herein, the term “aryl,” employed alone or in combination withother terms, means, unless otherwise stated, a carbocyclic aromaticsystem containing one or more rings (typically one, two or three rings)wherein such rings may be attached together in a pendent manner, such asa biphenyl, or may be fused, such as naphthalene. Examples includephenyl, anthracyl, and naphthyl.

As used herein, the term “aryl-(C₁-C₃)alkyl” refers to a functionalgroup wherein a one to three carbon alkylene chain is attached to anaryl group, e.g., —CH₂CH₂-phenyl or —CH₂-phenyl (benzyl). Specificexamples are aryl—CH₂— and aryl—CH(CH₃)—. The term “substitutedaryl-(C₁-C₃)alkyl” refers to an aryl-(C₁-C₃)alkyl functional group inwhich the aryl group is substituted. A specific example is substitutedaryl(CH₂)—. Similarly, the term “heteroaryl-(C₁-C₃)alkyl” refers to afunctional group wherein a one to three carbon alkylene chain isattached to a heteroaryl group, e.g., —CH₂CH₂-pyridyl. A specificexample is heteroaryl-(CH₂)—. The term “substitutedheteroaryl-(C₁-C₃)alkyl” refers to a heteroaryl-(C₁-C₃)alkyl functionalgroup in which the heteroaryl group is substituted. A specific exampleis substituted heteroaryl-(CH₂)—.

As used herein, the term “cycloalkyl,” by itself or as part of anothersubstituent refers to, unless otherwise stated, a cyclic chainhydrocarbon having the number of carbon atoms designated (i.e., C₃-C₆refers to a cyclic group comprising a ring group consisting of three tosix carbon atoms) and includes straight, branched chain or cyclicsubstituent groups. Examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Other examples are(C₃-C₆)cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

As used herein, the term “DavePhos” refers to2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl.

As used herein, the term “dvds” refers to1,3-divinyl-1,1,3,3-tetramethyl disiloxane.

As used herein, the term “halide” refers to a halogen atom bearing anegative charge. The halide anions are fluoride (F), chloride (CF),bromide (Br⁻), and iodide (I⁻).

As used herein, the term “halo” or “halogen” alone or as part of anothersubstituent refers to, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. As used herein, the term “heteroalkenyl” byitself or in combination with another term refers to, unless otherwisestated, a stable straight or branched chain monounsaturated ordiunsaturated hydrocarbon group consisting of the stated number ofcarbon atoms and one or two heteroatoms selected from the groupconsisting of O, N, and S, and wherein the nitrogen and sulfur atoms mayoptionally be oxidized and the nitrogen heteroatom may optionally bequaternized. Up to two heteroatoms may be placed consecutively. Examplesinclude —CH═CH—O—CH₃, —CH═CH—CH₂—OH, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃,and —CH₂—CH═CH—CH₂—SH.

As used herein, the term “heteroalkyl” by itself or in combination withanother term refers to, unless otherwise stated, a stable straight orbranched chain alkyl group consisting of the stated number of carbonatoms and one or two heteroatoms selected from the group consisting ofO, N, and S, and wherein the nitrogen and sulfur atoms may be optionallyoxidized and the nitrogen heteroatom may be optionally quaternized. Theheteroatom(s) may be placed at any position of the heteroalkyl group,including between the rest of the heteroalkyl group and the fragment towhich it is attached, as well as attached to the most distal carbon atomin the heteroalkyl group. Examples include: —O—CH₂—CH₂—CH₃,—CH₂—CH₂—CH₂—OH, —CH₂—CH₂—NH—CH₃, —CH₂—S—CH₂—CH₃, and —CH₂CH₂—S(═O)—CH₃.Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃, or —CH₂—CH₂—S—S—CH₃.

As used herein, the term “heterocycle” or “heterocyclyl” or“heterocyclic” by itself or as part of another substituent refers to,unless otherwise stated, an unsubstituted or substituted, stable, mono-or multi-cyclic heterocyclic ring system that consists of carbon atomsand at least one heteroatom selected from the group consisting of N, O,and S, and wherein the nitrogen and sulfur heteroatoms may be optionallyoxidized, and the nitrogen atom may be optionally quaternized. Theheterocyclic system may be attached, unless otherwise stated, at anyheteroatom or carbon atom that affords a stable structure. A heterocyclemay be aromatic or non-aromatic in nature. In certain embodiments, theheterocycle is a heteroaryl.

As used herein, the term “heteroaryl” or “heteroaromatic” refers to aheterocycle having aromatic character. A polycyclic heteroaryl mayinclude one or more rings that are partially saturated. Examples includetetrahydroquinoline and 2,3-dihydrobenzofuryl.

Examples of non-aromatic heterocycles include monocyclic groups such asaziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane,2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane,piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine,morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran,1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane,4,7-dihydro-1,3-dioxepin and hexamethyleneoxide.

Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl(such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl,thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl,isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyland 1,3,4-oxadiazolyl.

Examples of polycyclic heterocycles include indolyl (such as, but notlimited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl,tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl(such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl,phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin,dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but notlimited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl,1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-,5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, butnot limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl,benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl,acridinyl, pyrrolizidinyl, and quinolizidinyl.

The aforementioned listing of heterocyclyl and heteroaryl moieties isintended to be representative and not limiting.

As used herein, the term “IPr” refers to1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene.

As used herein, the term “IPr*OMe” refers to1,3-bis(2,6-bis-(diphenylmethyl)-4-methoxyphenyl)imidazol-2-ylidene.

As used herein, the term “ligand” refers to any organic or inorganicmolecule or ion that is capable of coordinating to a metal center. Incertain embodiments, the ligand comprises one or more lone electronpairs that can coordinate with a metal center.

As used herein, the term “precatalyst” refers to atransition-metal-containing complex that, under specific reactionconditions, is converted to an active cross-coupling catalyst. Incertain embodiments, the precatalyst is dimeric, i.e., contains twotransition metals per molecule. In other embodiments, the precatalyst ismonomeric, i.e., contains one transition metal per molecule. In yetother embodiments, conversion of the precatalyst to the activecross-coupling catalyst comprises contacting the precatalyst with aselected ligand.

As used herein, the term “QPhos” refers to1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene.

As used herein, the term “RuPhos” refers to2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl.

As used herein, the term “SPhos” refers to2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.

As used herein, the term “substituted” refers to that an atom or groupof atoms has replaced hydrogen as the substituent attached to anothergroup.

As used herein, the term “substituted alkyl,” “substituted cycloalkyl,”“substituted alkenyl” or “substituted alkynyl” refers to alkyl,cycloalkyl, alkenyl or alkynyl, as defined above, substituted by one,two or three substituents selected from the group consisting of halogen,-OH, alkoxy, tetrahydro-2-H-pyranyl, —NH₂, —N(CH₃)₂,(1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,—C(═O)OH, trifluoromethyl, —C♭N, —C(═O)O(C₁-C₄)alkyl, —C(═O)NH₂,—C(═O)NH(C₁-C₄)alkyl, —C(═O)N((C₁-C₄)alkyl)₂, —SO₂NH₂, —C(═NH)NH₂, and—NO₂, preferably containing one or two substituents selected fromhalogen, —OH, alkoxy, —NH₂, trifluoromethyl, —N(CH₃)₂, and —C(═O)OH,more preferably selected from halogen, alkoxy and —OH. Examples ofsubstituted alkyls include, but are not limited to, 2,2-difluoropropyl,2-carboxycyclopentyl and 3-chloropropyl.

For aryl, aryl-(C₁-C₃)alkyl and heterocyclyl groups, the term“substituted” as applied to the rings of these groups refers to anylevel of substitution, namely mono-, di-, tri-, tetra-, orpenta-substitution, where such substitution is permitted. Thesubstituents are independently selected, and substitution may be at anychemically accessible position. In certain embodiments, the substituentsvary in number between one and four. In another embodiment, thesubstituents vary in number between one and three. In yet anotherembodiment, the substituents vary in number between one and two. In yetanother embodiment, the substituents are independently selected from thegroup consisting of C₁₋₆ alkyl, —OH, C₁₋₆ alkoxy, halo, amino, acetamidoand nitro. As used herein, where a substituent is an alkyl or alkoxygroup, the carbon chain may be branched, straight or cyclic.

As used herein, the term “XPhos” refers to2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

Ranges: throughout this disclosure, various aspects of the invention canbe presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theinvention. Accordingly, the description of a range should be consideredto have specifically disclosed all the possible sub-ranges as well asindividual numerical values within that range. For example, descriptionof a range such as from 1 to 6 should be considered to have specificallydisclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual and partialnumbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6.This applies regardless of the breadth of the range.

Description

The present invention relates to the unexpected discovery of noveltransition-metal precatalysts that are useful in preparing activecoupling catalysts. In certain embodiments, the precatalysts of theinvention are air-stable and moisture-stable. The present inventionprovides methods of making and using the precatalysts of the invention.

In one aspect, a key feature in the effectiveness of the Pd(II)precatalysts is the rate and efficiency of their conversion into themonoligated L-Pd(0) active species under the reaction conditions. Forexample, the efficiency of Nolan type (η³-allyl)Pd(NHC)(Cl) precatalystsrelates to two factors: (i) the rate of activation of the ligatedprecatalyst scaffold to form the catalytically active L-Pd(0) speciesand (ii) comproportionation between L-Pd(0) and the startingprecatalyst, which forms a Pd(I) dimer of the form(μ-allyl)(μ-Cl)Pd₂(L)₂ and removes the L-Pd(0) from the reaction mixture(FIG. 4). In certain embodiments, monomeric precatalysts withsubstituents in the 1-position of the allyl ligand are active becausethey are less likely to comproportionate with monoligated L-Pd(0) toform Pd(I) dimers. As a result, the active L-Pd(0) preferably undergoesoxidative addition with the substrate, rather than be sequestered intothe less reactive dimeric form. However, even in the case of the mostactive 1-substituted precatalysts some Pd (˜35%) may be trapped in theform of the Pd(I) dimer.

As demonstrated herein, improved precatalysts can be designed by furtherincreasing the barrier to comproportionation. In certain embodiments,the speed at which the Pd(II) precatalyst is converted into Pd(0) isincreased, so that the conversion of Pd(II) to Pd(0) is significantlyfaster than deleterious comproportionation between Pd(II) and Pd(0) toform Pd(I). In certain embodiments, the precatalysts of the inventiontake part in catalysis without forming significant amounts of inactivePd(I) dimers. In other embodiments, the precatalysts of the inventionare compatible with phosphine or N-heterocyclic carbene (NHC) ligands.

The present disclosure provides the first comprehensive insight into theconversion of Pd(II) to Pd(0) for precatalysts of the type(η³-allyl)Pd(IPr)(Cl) under conditions that are typically used for theSuzuki-Miyaura reaction. The present disclosure further provides the newprecatalyst (η³-1-^(t)Bu-indenyl)Pd(IPr)(Cl), which is significantlymore efficient than (η³-cinnamyl)Pd(IPr)(Cl) for the Suzuki-Miyaurareaction with both weak and strong base. In certain embodiments, thedimeric compound (η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂is used as aprecatalyst in combination with an appropriate ligand, and is alsosuperior to its dimeric analogue (η³-cinnamyl)₂(μ-Cl)₂Pd₂.

In certain embodiments, the novel precatalyst scaffold of the inventioncan be used at least in the following reactions: Suzuki-Miyaura,Buchwald-Hartwig, Kumada, Sonogashira, Heck, C—S and C—O bond formation,α-arylation of aldehydes, α-arylation of ketones, α-arylation of amides,α-arylation of heterocycles, and anaerobic oxidation of alcohols.

Synthesis of Pd(II) Indenyl Complexes

The current synthesis of the indenyl dimer (η³-indenyl)₂(μ-Cl)₂Pd₂ (3a),which can be converted into the monomeric compound(η³-indenyl)Pd(IPr)(Cl) (4a-IPr) through reaction with the appropriatefree ligand, requires three steps and utilizes air-sensitive reagents.

As demonstrated herein, this reaction may be performed as a one-potsynthesis under aerobic conditions, without the use of air sensitivereagents (FIG. 5). In the synthesis of the invention, one equivalent ofNa₂PdCl₄ (generated in situ from PdCl₂ and two equivalents of NaCl) wastreated with indene and Na₂CO₃ in MeO H. The mixture was stirred for twohours at room temperature. During this time, a brown solid precipitatedout of solution, which was then filtered and washed successively withwater and diethyl ether to give 3a in high yield (84%) and purity. Thismethod was also used to prepare three related substituted indenyldimers, (η³-1-R-indenyl)₂(μ-Cl)₂Pd₂ (R=Me (3b), ^(i)Pr (3c) or ^(t)Bu(3d)), in good yield (>70% in all cases), by starting with theappropriately substituted indene. Alternatively NaHCO₃ can be used asthe base in the synthesis of 3d, with no decrease in yield.

Subsequently, the dimeric complexes were treated with two equivalents ofIPr to generate the monomeric complexes (η³-1-R-indenyl)Pd(IPr)(Cl) (R=H(4a-IPr), Me (4b-IPr), ^(i)Pr (4c-IPr) or ^(t)Bu (4d-IPr)) in high yield(˜80%). The new complexes 4b-IPr, 4c-IPr and 4d-IPr were fullycharacterized. Overall, the novel two-step synthesis of 4a-IPr is asignificant improvement on the earlier reported synthesis.

Activation of Pd(II) to Pd(0)

In certain embodiments, the rate determining step in the formation ofPd(0) from a (η³-allyl)Pd(IPr)(Cl) involves the transformation of theη³-allyl type ligand into an η³-allyl ligand. In other embodiments, thetransformation is easier for 1-substituted species due to stericfactors. In yet other embodiments, the transformation proceeds at ahigher rate for 1,3-disubstituted η³-allyl ligands, such as η³-indenylligands.

The rates of activation of complexes containing η³-allyl, η³-cinnamyland Θ³-indenyl ligands were compared, and the results obtained allowedfor the elucidation of the mechanism for the conversion of Pd(II) intoPd(0). The rates of conversion of the Pd(II) complexes 1-IPr, 2-IPr,4a-IPr and 4d-IPr into Pd(0) were studied by treating these compoundswith base in the presence of ten equivalents of1,3-divinyl-1,1,3,3-tetramethyldisiloxane (dvds) (Table 1). In allcases, the product of these reactions are the Pd(0) complex(IPr)Pd(dvds), along with various different organic by-products (Table2). These reactions model the initial reduction from Pd(II) to Pd(0) incatalysis, where oxidative addition to the unstable monoligated Pd(0)complex subsequently occurs to start the catalytic process.

Three different types of reaction conditions, which are relevant tocatalysis, were examined. The first set of conditions involved KO^(t)Buas the base and d₈-^(i)PrOH as the solvent (a small amount of d₈-THF wasalso added to ensure homogenous reaction conditions). The second set ofconditions involved K₂CO₃ and d₄-MeOH as the solvent. Under theseconditions, K₂CO₃ was not soluble and1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) was used as asolubilizing agent. The third set of conditions involved KO^(t)Bu as thebase and d₄-MeOH as the solvent.

TABLE 1 Rates of activation of 1-IPr, 2-IPr, 4a-IPr or 4d-IPr in thepresence of dvds.^(a)

PhB(OH)₂ Rate of activation k_(obs) (s⁻¹)^(e) Base Solvent present 1-IPr2-IPr 4a-IPr 4d-IPr KO^(t)Bu d₈-^(i)PrOH^(b) No 5.6 ± 0.1 * 10⁻⁴ 3.80 ±0.03 * 10⁻³ >7.7 * 10⁻³ >7.7 * 10⁻³ (4.8 ± 0.1 * 10⁻³)^(f) (5.3 ± 0.2 *10⁻³)^(f) KO^(t)Bu d₄-MeOH No 1.80 ± 0.02 * 10⁻³ 5.1 ± 0.1 * 10⁻⁴ >7.7 *10⁻³ >7.7 * 10⁻³ (5.3 ± 0.2 * 10⁻³)^(f) (5.7 ± 0.1 * 10⁻³)^(f) K₂CO₃d₄-MeOH^(c) No 9.6 ± 0.2 * 10⁻⁴ 4.2 ± 0.1 * 10⁻⁴ >7.7 * 10⁻³ >7.7 * 10⁻³(4.7 ± 0.1 * 10⁻³)^(f) (5.0 ± 0.2 * 10⁻³)^(f) K₂CO₃ d₄-MeOH^(c) Yes^(d)2.4 ± 0.1 * 10⁻⁴ 1.4 ± 0.2 * 10⁻⁴ 7.2 ± 0.1 * 10⁻⁴ 7.6 ± 0.1 * 10⁻⁴^(a)Reaction conditions: 0.0087 mmol 1-IPr, 2-IPr, 4a-IPr or 4d-IPr0.087 mmol base, 0.087 mmol of dvds in 500 μL of solvent. ^(b)100 μL ofd₈-THF was added along with only 400 μL of ^(i)PrOH. ^(c)Two equivalentsof 18-crown-6 (compared to K₂CO₃) were added to solubilize K₂CO₃.^(d)0.087 mmol precatalyst, 0.087 mmol phenylboronic acid, 0.096 mmolbase, 0.087 mmol dvds in 500 μL d₄-MeOH. ^(e)All rates are the averageof at least two runs. ^(f)Experiments performed at 0° C.

TABLE 2 By-products from activation of 1-IPr, 2-IPr, 4a-IPr or 4d-IPr inthe presence of dvds.^(a) PhB(OH)₂ By-products from activation BaseSolvent present 1-IPr 2-IPr 4a-IPr 4a-IPr KO^(t)Bu d₈-^(i)PrOH Nopropene, allylbenzene, indene, 1-^(t)Bu-indene, acetone acetone acetoneacetone KO^(t)Bu d₄-MeOH No propene, allylbenzene, indene,1-^(t)Bu-indene, formaldehyde formaldehyde formaldehyde formaldehydeK₂CO₃ d₄-MeOH No propene, allylbenzene, indene, 1-^(t)Bu-indene,formaldehyde formaldehyde formaldehyde formaldehyde K₂CO₃ d₄-MeOH Yespropene, allylbenzene, indene, 1-^(t)Bu-indene, formaldehydeformaldehyde formaldehyde formaldehyde ^(a)The same reaction conditionsdescribed in Table 1 were utilized, with the exception that protiorather than deuterated solvents were utilized to determine the organicby-products originating from the solvent.

The indenyl complexes 4a-IPr and 4d-IPr were activated the fastest inall cases. In many instances, the activation was so fast that only aminimum rate could be estimated at 25° C. using ¹H NMR spectroscopy. Aseries of reactions analogous to those described in Table 1 at 0° C.,allowed us to establish that 4d-IPr activates slightly faster than4a-IPr. As expected, using the traditional cross-coupling conditions forthe Suzuki-Miyaura reaction of KO^(t)Bu in d₈-^(i)PrOH, the cinnamylspecies 2-IPr underwent significantly faster activation than theunsubstituted species 1-IPr. However, under the conditions developed forcross-coupling with weak base (K₂CO₃ in d₄-MeOH), 1-IPr underwent morerapid activation than 2-IPr. When the base was changed from K₂CO₃ toKO^(t)Bu in d₄-MeOH, slightly faster activation was observed for both1-IPr and 2-IPr, and the rate for the unsubstituted species 1-IPr wasagain faster than for 2-IPr.

The organic byproducts of activation were identified and quantifiedusing either ¹H or ¹³C NMR spectroscopy. Under all conditions, propene,allylbenzene, indene and 1-^(t)Bu-indene were observed as by-products inactivation studies using 1-IPr, 2-IPr, 4a-IPr and 4d-IPr, respectively,in >95% yield. In addition, for all reactions performed in ^(i)PrOH,acetone was formed in high yield as determined using ¹³C NMRspectroscopy. Without wishing to be limited by any theory, in reactionsperformed in MeOH formaldehyde may be a byproduct.

In certain embodiments, the appearance of related byproducts in theactivation of 1-IPr, 2-IPr, 4a-IPr and 4d-IPr suggests that thereactions follow a similar mechanism. Consistent with this observation,all reactions were first order in Pd. A series of experiments using1-IPr as a representative compound indicated that, regardless of thesolvent and choice of base, the activation of 1-IPr was 1^(st) order inbase (FIG. 6). In agreement with the concentration of base effecting therate of activation, when experiments were performed in the presence often equivalents of phenylboronic acid (a coupling partner in theSuzuki-Miyaura reaction), slower rates were observed. However, thereaction byproducts were still the same, indicating that a pathway foractivation that involves initial transmetalation of the boronic acid,followed by reductive elimination, does not occur. Without wishing to belimited by any theory, the boronic acid reduces the effectiveconcentration of the base, rather than playing a direct role inactivation.

In the absence of dvds, the Pd containing products of the activation of1-IPr, 2-IPr and 4a-IPr were Pd(I) dimers with bridging allyl or indenylligands, while the organic byproducts were the same as those observedwith dvds. However, the Pd(I) dimers were not soluble under the reactionconditions, which precluded careful kinetic analysis of the data.Nevertheless, qualitative analysis indicated that activation experimentsperformed in the absence of dvds gave the same trends as those in thepresence of dvds, with the indenyl complex 4a-IPr activatingsignificantly faster than either 1-IPr or 2-IPr (Table 3). Withoutwishing to be limited by any theory, conclusions made about the rate ofactivation in the presence of dvds are relevant to the catalytic systemwhich does not contain dvds.

TABLE 3 Rates of activation of 1-IPr, 2-IPr or 4a-IPr in the absence ofdvds.^(a)

Time to completion (minutes)^(e) Base Solvent 1-IPr 2-IPr 4a-IPrKO^(t)Bu d₈-^(i)PrOH^(b) 150  90 40 KO^(t)Bu d₄-MeOH 120 150 30 K₂CO₃^(c) d₄-MeOH 160 180 40 ^(a)Reaction conditions: 0.0087 mmol 1-IPr,2-IPr or 4a-IPr, 0.087 mmol of base in 500 μL of solvent ^(b)100 μL ofd₈-THF was added along with only 400 μL of ^(i)PrOH. ^(c)Two equivalentsof 18-crown-6 (compared to K₂CO₃) were added to solubilize the K₂CO₃.^(d)0.0087 mmol precatalyst, 0.087 mmol phenylboronic acid, 0.096 mmolbase in 500 μL d₄-MeOH ^(e)All times to complexes are the average of atleast two runs.

Catalytic Experiments and Pd(I) Dimer Formation

As demonstrated herein, the indenyl systems 4a-IPr and 4d-IPr werereduced faster from Pd(II) to Pd(0) than the cinnamyl system 2-IPr,under varying conditions. In certain embodiments, 4a-IPr and 4d-IPr arebetter precatalysts for the Suzuki-Miyaura reaction if deleterious sidereactions that remove Pd(0) from the catalytic mixture are minimized.

2-IPr and the family of indenyl complexes 4a-IPr-4d-IPr were tested asprecatalysts for a Suzuki-Miyaura reaction involving an aryl chlorideusing both weak (K₂CO₃) and strong (KO^(t)Bu) bases (FIG. 3). Theresults show that the indenyl-supported precatalysts were more activethan the cinnamyl supported species under both sets of conditions, whichis consistent with faster reduction from Pd(II) to Pd(0) under thecatalytic conditions. Furthermore, as the size of the substituent on theη³-indenyl ligand was increased the precatalysts became more active,with 4d-IPr being the most efficient precatalyst.

FIG. 3 illustrates the % yield obtained using the indenyl complexes4a-IPr, 4b-IPr, 4c-IPr and 4d-IPr as precatalysts for the Suzuki-Miyaurareaction of 4-chlorotoluene with phenylboronic acid, using both weak(K₂CO₃) and strong (KO^(t)Bu) base in a 19:1 MeOH:THF mixture(Conditions A and B, respectively). For comparison, both Nolan's(η³-cinnamyl)Pd(Cl)(IPr) (also known as 2a-IPr) and Organ's(3-chloropyridine)Pd(Cl)₂(IPr) (also known as PEPPSI-IPr) precatalystswere included. The same trends in precatalyst performance were observedunder both sets of reaction conditions. All of the indenyl supportedprecatalysts were more active than 2a-IPr, and both 4c-IPr and 4d-IPrwere also significantly more active than PEPPSI-IPr. Theindenyl-supported precatalysts become more active as the size of thesubstituent on the indenyl ligand was increased, with 4d-IPr being themost efficient system.

In the case of η³-allyl systems, the tendency of the precatalyst andmonoligated Pd(0) to comproportionate to generate a Pd(I) dimer, a lessreactive form during catalysis, decreased as the steric bulk on theη³-allyl ligand increased (FIG. 4). In order to probe if a similareffect was occurring in indenyl systems, the tendency of the leaststerically bulky (4a-IPr) and most sterically bulky (4d-IPr)precatalysts to dimerize was examined.

The unsubstituted indenyl dimer 7-IPr was prepared in 85% yield throughthe treatment of 4a-IPr with K₂CO₃ in EtOH (Eq 1). Compound 7-IPr wasfully characterized, including by X-ray crystallography. In contrast tocomplex 4a-IPr, no dimer formation was observed when 4d-IPr was treatedwith K₂CO₃ (Eq 2). Instead, only Pd(0) products were observed in thereaction mixture. This observation suggests that Pd(I) dimer formationvia comproportionation is more difficult for indenyl systems withgreater steric bulk.

Catalysis

In order to confirm that indenyl-based systems were superior to thecinnamyl precatalyst 2-IPr, a head to head comparison was performedbetween 4d-IPr and 2-IPr using a range of different substrates for theSuzuki-Miyaura reaction using both a weak and strong base (Table 4). Inall cases 4d-IPr was a significantly better precatalyst than 2-IPr andwas able to couple a variety of different aryl chloride substrates atroom temperature. This included substrates with deactivating electrondonating groups and substituents in the ortho positions. The improvementfrom 2-IPr to 4d-IPr was most pronounced using weak base compared tostrong base and occurred regardless of the catalyst loading. Nolan typeprecatalysts had not been shown to afford full conversion forSuzuki-Miyaura reactions with weak base, so the quantitative yieldsobtained with 4d-IPr represent a significant improvement and couldexpand the range of viable substrates with this catalytic system.

TABLE 4 Yields^(a) of product for Suzuki-Miyaura reactions^(b) catalyzedby 2-IPr and 4d-IPr.

Cat. Loading Time % Yield for Precatalysts Product Base (mol %) (min) 24d-IPr

KO^(t)Bu K₂CO₃ 0.5 1.0 120  45 21 29 >99 >99

KO^(t)Bu K₂CO₃ 0.5 1.0 120 120 46 15 >99 >99

KO^(t)Bu K₂CO₃ 0.5 1.0  45  30 25 18 >99 >99

KO^(t)Bu K₂CO₃ 0.1 0.2  30  60 54 21 >99 >99

KO^(t)Bu K₂CO₃ 0.1 0.2 120  60 25 21 >99 >99

KO^(t)Bu K₂CO₃ 0.5 1.0 120 120 41 22 >99 >99

KO^(t)Bu K₂CO₃ 0.1 0.2  60 120 43 35 >99 >99 ^(a)Yields were calculatedusing gas chromatography with naphthalene as an interal standard and arethe average of two runs. ^(b)Reaction conditions KO^(t)Bu: Methanolsolution containing 0.5263M aryl chloride, 0.5526M boronic acid, 0.5789MKO^(t)Bu and 0.2632M naphthalene (950 μL), THF solution containing 0.05M[Pd] (50 μL). Reaction conditions using K₂CO₃: Methanol solutioncontaining 0.5263M aryl chloride, 0.5526M boronic acid and 0.2632Mnaphthalene (950 μL), THF solution containing 0.1M [Pd] (50 μL), 104 mgK₂CO₃ added to each reaction.

In Nolan's cinnamyl system, the ligand free precursor,(η³-cinnamyl)₂(μ-Cl)₂Pd₂ may be converted into the ligated precatalystin situ. This allows for a variety of different ligands to be rapidlyscreened for a reaction, without the need for the synthesis or isolationof a family of well-defined precatalysts.

The catalytic activity of an in situ generated solution of(η³-cinnamyl)₂(μ-Cl)₂Pd₂ and two equivalents of IPr was compared with anin situ generated solution of (ηn³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) andtwo equivalents of IPr using both weak and strong bases (Table 5). Theindenyl scaffold performed significantly better than Nolan's system.This suggests that not only does do η³-indenyl systems give moreefficient isolated precatalysts but that they are a better scaffold forthe screening of new ligands in situ than the traditional cinnamylsystem. Without wishing to being bound to any theory, the increasedactivity of precatalysts with more sterically demanding substituents onthe indenyl ligand is due to the fact that Pd(I) dimers with bridgingindenyl ligands are less likely to form in these cases.

TABLE 5 Yields^(a) of product for the Suzuki-Miyaura reaction^(b)catalyzed by an in situ generated solution of (η³-cinnamyl)₂(μ-Cl)₂Pd₂and IPr and an in situ generated solution of(η³-1-^(t)Bu-indenyl)₂(μ-C1)₂Pd₂ and IPr.

Time % Yields for Precatalysts Base (min) (μ-C1)₂Pd₂(η³-cinnamyl)₂(μ-C1)₂Pd₂(η³-1-^(t)Bu-indenyl)₂ KO^(t)Bu 15 <1 7 30 <1 30 45 3 58 60 576 120 8 >99 K₂CO₃ 30 <1 37 60 3 79 90 5 >99 ^(a)Yields were calculatedusing gas chromatography with naphthalene as an internal standard andare the average of two runs. ^(b)Reaction conditions KO^(t)Bu: Methanolsolution containing 0.5263M aryl chloride, 0.5526M boronic acid, 0.5789MKO^(t)Bu and 0.2632M naphthalene (950 μL), THF solution containing 0.05M[Pd]_(Tot), 0.05M IPr (solution allowed to stir for one hour prior touse, 50 μL). Reaction conditions using K₂CO₃: Methanol solutioncontaining 0.5263M aryl chloride, 0.5526M boronic acid and 0.2632Mnaphthalene (950 μL), THF solution containing 0.1M [Pd]_(Tot), 0.1M IPr(solution allowed to stir for one hour prior to use, 50 μL), 104 mgK₂CO₃ added to each reaction.

To demonstrate that the present precatalyst scaffold is compatible withstate of the art NHC ligands, Suzuki-Miyaura reactions that generatetetra-ortho-substituted biaryl products were performed (FIG. 7). Forthis type of challenging reaction, the sterically hindered ancillaryligand IPr*^(OMe)(IPr*^(Ome)=1,3-bis(2,6-bis-(diphenylmethyl)-4-methoxyphenyl)imidazol-2-ylidene)is required. The complex (η³-1-^(t)Bu-indenyl)Pd(IPr*^(Ome))(Cl) or4d-IPr^(*OMe) was prepared through the reaction of IPr*^(OMe) with 3d.Using 4d-IPr^(*OMe) as a precatalyst, a number oftetra-ortho-substituted products were prepared in high yield. When arylbromides were used as substrates, reactions took place at lowertemperature (80° C.), compared to cinnamyl systems supported byIPr*^(Ome). Furthermore, by increasing the catalyst loading to 1.0 mol%, aryl chlorides were used as substrates under the same reactionconditions. In certain embodiments, this method utilizes the mildestconditions reported to produce tetra-ortho-substituted products in highyields using aryl chlorides.

Catalytic Reactions with Phosphine Supported Complexes

Experiments were run to explore the scope of phosphines as ligands. Tothis end, a family of phosphine ligated complexes with the generalstructure (η³-^(t)Bu-indenyl)Pd(L)(Cl) were synthesized (FIG. 8).Coordination was achieved through the addition of two equivalents ofligand to the dimeric precursor, 3d, to afford a variety of precatalystswith excellent yields. A number of state of the art ligands, includingseveral Buchwald-type phosphines, were successfully coordinated to thedimeric scaffold.

With these complexes in hand, the phosphine supported systems werescreened for currently challenging cross-coupling reactions.Heterocycles are commonly found in pharmaceuticals and natural productsbut traditionally represent difficult substrates for cross- coupling.For example, Suzuki-Miyaura reactions that employ boronic acids in the2-position of 5-membered heterocycles are particularly challenging dueto their tendency to undergo rapid protodeboronation. Therefore, a rapidand efficient precatalyst must be used to afford full conversion toproduct. Using (η³-1-^(t)Bu-indenyl)Pd(XPhos)(Cl) (4d-XPhos) as theprecatalyst, a range of 2-heterocyclic boronic acids were successfullycoupled to produce biaryl products in excellent yields under mildreaction conditions (FIG. 9). The present precatalysts, which givecomparable or superior performance to the best known systems for thisreaction, are also tolerant to a wide range of functional groups on thearyl chloride, including phenols, Boc-protected anilines and freeamines.

The compatibility of Pd-catalyzed cross-coupling methodology withsubstrates containing acidic, free N-H moieties is a common syntheticproblem. Employing (η³-1-^(t)Bu-indenyl)Pd(SPhos)(Cl) (4d-SPhos), yieldsof greater than 90% for reactions were obtained where the aryl chloridewas either indazole or benzimidazole (FIG. 10). With the presentcatalyst system, the temperature could be lowered slightly (80° C.),with excellent yields obtained in 15 hours. In certain embodiments, thismethodology supports the use of heteroaromatic boronic acids.

After the Suzuki-Miyaura reaction, the Buchwald-Hartwig coupling is thenext most commonly performed cross-coupling reaction in the synthesis ofpharmaceuticals. (η³-1-^(t)Bu-indenyl)Pd(RuPhos)(Cl) (4d-RuPhos)successfully generated a selection of symmetrical and unsymmetricaltertiary amines in good to excellent yield (FIG. 11). Various arylchlorides containing heteroatoms and ortho-substituents were compatiblewith the present system.

The monoarylation of aryl methyl ketones is important due to theprevalence of α-aryl carbonyl moieties in organic compounds withinteresting pharmacological and biological properties. However, this isa challenging reaction due to the possibility for diarylation of theketone. Using (η³-1-^(t)Bu-indenyl)Pd(XPhos)(Cl) (4d-XPhos) excellentresults were observed for the monoarylation of a variety of methylketones under moderate conditions (FIG. 12). Using a 1:1 THF/MeOHmixture and KO^(t)Bu as base, heterocyclic moieties in both the arylchloride and aryl methyl ketone were tolerated with yields greater than90% in each case. In fact, in two cases, the products containedheterocyclic fragments in both coupling partners.

The precatalysts of the invention were used in cross-coupling ofunactivated alkyl coupling partners. Using the literature systems, theSuzuki-Miyaura of alkyl trifluoroboronates (as boronic acid mimics) witharyl chlorides generally requires high catalyst loadings (5-10 mol %),high temperatures (110° C.) and long reaction times (24-48 hours). Byusing (η³-1-^(t)Bu-indenyl)Pd(P^(t)Bu₃)(Cl) (4d-P^(t)Bu₃) as theprecatalyst, sizable improvements on the existing protocol wereachieved. Specifically, in some cases catalyst loadings could be reducedto 1 mol % and shorter reaction times (8 hours) utilized. By using4d-P^(t)Bu₃, both linear and cyclic alkyl trifluoroboronates salts couldbe coupled to a variety of aryl chlorides, including one example of anitrogen containing heterocycle (FIG. 13). In fact, when potassiumcyclopropyl trifluoroboronate was used, the temperature could be loweredto 40° C. without any loss in activity (96% yield).

To demonstrate that (η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) is suitablefor rapid ligand screening, without the need for the isolation ofwell-defined precatalysts, a series of catalytic reactions wereperformed using an in situ generated solution of 3d and two equivalentsof ligand. When 3d was mixed with the appropriate ligand for 10 minutesat RT excellent activity was observed for all of the reactions describedherein with isolated precatalysts. Comparative experiments betweensystems containing 3d and IPr and Nolan's cinnamyl dimer and IPr, showedthat superior catalytic activity was observed with 3d. In fact, asuccessful reaction was achieved without premixing 3d and ligand; Eq 3illustrates a one-pot Suzuki-Miyaura reaction where the precatalyst wasgenerated during the reaction. Under these conditions, there was no lossin activity compared to both the in situ generated and isolated versionsof 4d-XPhos. In certain embodiments, the present methodology allowsaccess to a variety of general and rapid screening procedures.

Precatalysts

In one aspect, the invention provides a precatalyst of formula (I), or asalt or solvate thereof:

wherein in (I) each occurrence of M is independently a transition metal;each occurrence of X is independently a ligand; each occurrence of R isindependently selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl andsubstituted heteroaryl, with the proviso that each of the 5-memberedrings is substituted with at least one independently selected R; Z isCH, CR or N, with the proviso that 0-2 Z groups are N; or the Z groupsat the 5- and 6-positions are null and the Z groups at the 4- and7-positions are independently R; and n is 1, 2, 3, or 4.

In certain embodiments each occurrence of X is independently selectedfrom the group consisting of halide, trifluoromethanesulfonate(triflate), tosylate, mesylate, tetrafluoroborate (⁻BF₄),tetraphenylborate (⁻BPh₄), hexafluorophosphate (⁻PF₆), acetate,trifluoroacetate (TFA), acetonitrile, tetrahydrofuran (THF),dichloromethane (DCM) and water.

In other embodiments, X is an anionic ligand. In yet other embodiments,X is a monocharged anionic ligand.

In certain embodiments, each occurrence of M is independently selectedfrom the group consisting of Pd, Ni and Pt. In other embodiments, thetwo occurrences of M in (I) are identical. In yet other embodiments, thetwo occurrences of M in (I) are Pd. In yet other embodiments, the twooccurrences of M in (I) are Ni. In yet other embodiments, the twooccurrences of M in (I) are Pt.

In certain embodiments, the two occurrences of X in (I) are identical.In other embodiments, the two occurrences of X in (I) are chloride. Inanother embodiments, the two occurrences of X in (I) are bromide. In yetother embodiments, the two occurrences of X in (I) are fluoride. In yetother embodiments, the two occurrences of X in (I) are iodide. In yetother embodiments, the two occurrences of X in (I) aretrifluoromethanesulfonate (triflate). In yet other embodiments, the twooccurrences of X in (I) are mesylate. In yet other embodiments, the twooccurrences of X in (I) are tosylate. In yet other embodiments, the twooccurrences of X in (I) are identical and selected from the groupconsisting of tetrafluoroborate (⁻BF₄), tetraphenylborate (⁻BPh₄),hexafluorophosphate (⁻P F₆), acetate, trifluoroacetate (TFA),acetonitrile, tetrahydrofuran (THF), dichloromethane (DCM) and water.

In certain embodiments, the two ligands comprising a 5-membered ring areidentical. In other embodiments, the two ligands comprising a 5-memberedring are not identical.

In certain embodiments, each of the 5-membered rings is substituted withat least one R selected from the group consisting of an alkyl andsubstituted alkyl. In other embodiments, each of the 5-membered rings issubstituted with at least one methyl group. In yet other embodiments,each of the 5-membered rings is substituted with at least one isopropylgroup. In yet other embodiments, each of the 5-membered rings issubstituted with at least one tent-butyl group.

In certain embodiments, the 1- or 3-position of each of the 5-memberedrings is substituted with at least one R selected from the groupconsisting of alkyl and substituted alkyl. In other embodiments, the 1-or 3-position of each of the 5-membered rings is substituted with amethyl group. In yet other embodiments, the 1- or 3-position of each ofthe 5-membered rings is substituted with an isopropyl group. In yetother embodiments, the 1- or 3-position of each of the 5-membered ringsis substituted with a tent-butyl group.

In certain embodiments, the 2-position of each of the 5-membered ringsis substituted with at least one R selected from the group consisting ofalkyl and substituted alkyl. In other embodiments, the 2-position ofeach of the 5-membered rings is substituted with a methyl group. In yetother embodiments, the 2-position of each of the 5-membered rings issubstituted with an isopropyl group. In yet other embodiments, the2-position of each of the 5-membered rings is substituted with atent-butyl group.

In certain embodiments, each occurrence of Z is independently selectedfrom the group consisting of CH and CR, so the precatalyst of formula(I) is a substituted indenyl complex.

In certain embodiments, n is 1. In other embodiments, n is 2. In yetother embodiments, n is 3. In yet other embodiments, n is 4.

In another aspect, the invention provides a precatalyst of formula (II), or a salt or solvate thereof:

wherein in (II):M is a transition metal; X is a ligand; each occurrence of R isindependently selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl andsubstituted heteroaryl, with the proviso that at least one R is asubstituent in the 5-membered ring; Z is CH, CR or N, with the provisothat 0-2 Z groups are N; or the Z groups at the 5- and 6-positions arenull and the Z groups at the 4- and 7-positions are independently R; Lis a monodentate or bidentate ligand; and n is 1, 2, 3, or 4.

In certain embodiments, L is a bidentate ligand. In other embodiments, Lis a bidentate ligand, and X coordinates to M. In yet other embodiments,L is a bidentate ligand and X is absent or does not coordinate to M(i.e., there is no coordination between X and M). In yet otherembodiments, the two coordinating centers in the bidentate ligand L arecoordinated with M.

In certain embodiments, each occurrence of X is independently a weaklycoordinating ligand. In other embodiments, each occurrence of X isindependently selected from the group consisting of halide,trifluoromethanesulfonate (triflate), tosylate, mesylate,tetrafluoroborate (⁻BF₄), tetraphenylborate (⁻BPh₄), hexafluorophosphate(⁻PF₆), acetate, trifluoroacetate (TFA), acetonitrile, tetrahydrofuran(THF), dichloromethane (DCM) and water. In other embodiments, X is ananionic ligand. In yet other embodiments, X is a monocharged anionicligand.

In certain embodiments, M is selected from the group consisting of Pd,Ni and Pt. In other embodiments, M is Pd. In yet other embodiments, M isNi. In yet other embodiments, M is Pt.

In certain embodiments, X is chloride. In other embodiments, X isbromide. In yet other embodiments, X is fluoride. In yet otherembodiments, X is iodide. In yet other embodiments, X is triflate. Inyet other embodiments, X is mesylate. In yet other embodiments, X istosylate.

In certain embodiments, L is at least one selected from the groupconsisting of a phosphine, a N-heterocyclic carbene, a N-containingligand, an 0-containing ligand, and a S-containing ligand.

In certain embodiments, L is selected from the group consisting ofoptionally substituted 1,3-dihydro-2H-imidazol-2-ylidene, optionallysubstituted 1,3,4,5-tetrahydro-2H-imidazol-2-ylidene, and optionallysubstituted 1,2,4-triazol-5-ylidene. In other embodiments, L is1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene.

In certain embodiments, L is PR′R″R″′, wherein R″, R″ and R′″ areindependently selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl andsubstituted heteroaryl, wherein two or three R substituents may beoptionally covalently linked to form a cyclic structure with P.

In certain embodiments, L is at least one selected from the groupconsisting of AmPhos (di-t-butylphosphino-4-dimethylaminobenzene),DavePhos (2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl),^(tBu)DavePhos(2-Di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl), QPhos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene), RuPhos(2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl), SPhos(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl), XPhos(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), ^(tBu)XPhos(2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl), ^(Me4tBu)XPhos(2-Di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl),BrettPhos(2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl),^(tBu)BrettPhos (2-(Di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl), ^(Ad)BrettPhos(2-(Diadamantylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl), Me-DalPhos(2-(Di-1-adamantylphosphino) phenylpiperidine), Mor-DalPhos(Di(1-adamantyl)-2-morpholinophenylphosphine),Di(1-adamantyl)-1-piperidinyl-phenylphosphine, triphenylphosphine,tri(o-tolyl) phosphine, tricyclohexylphosphine andtri(t-butyl)phosphine.

In certain embodiments, L is a bidentate phosphine ligand. In otherembodiments, L is selected from the group consisting of1,1′-bis(diphenylphosphino) ferrocene (DPPF),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), 4,6-bis(diphenylphosphanyl)-10H-phenoxazine (NiXantPhos),1,2-bis(diphenylphosphino)ethane (dppe),1,1-bis(diphenylphosphino)methane (dppm),1,3-bis(diphenylphosphino)propane (dppp),1,4-bis(diphenylphosphino)butane (dppb),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),bis[(2-diphenylphosphino)phenyl] ether (DPEPhos),1,2-bis(dichlorophosphino) ethane, and1,2-bis(dicyclohexylphosphino)-ethane (dcpe).

In certain embodiments, L is NR′R″R′″, wherein R″, R″ and R″″ areindependently selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl andsubstituted heteroaryl, wherein two or three R substituents may beoptionally covalently linked to form a cyclic structure with N.

In certain embodiments, L is R′OR″, wherein R″ and R″ are independentlyselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl andsubstituted heteroaryl, wherein R′ and R″ may be optionally covalentlylinked to form a cyclic structure with 0. In other embodiments, L is anoptionally substituted furan or tetrahydrofuran. In yet otherembodiments, L is an ester, ketone or aldehyde.

In certain embodiments, L is R′ SR″, wherein R″ and R″ are independentlyselected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl andsubstituted heteroaryl, wherein R′ and R″ may be optionally covalentlylinked to form a cyclic structure with S. In other embodiments, L is anoptionally substituted thiophene or tetrahydrothiophene. In yet otherembodiments, L is an thioester, thioketone or thioaldehyde.

In certain embodiments, the 5-membered ring is substituted with at leastone R selected from the group consisting of alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl,substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl andsubstituted heteroaryl. In other embodiments, the 5-membered ring issubstituted with at least one R selected from the group consisting of analkyl and substituted alkyl. In yet other embodiments, the 5-memberedring is substituted with at least one methyl group. In yet otherembodiments, the 5-membered ring is substituted with at least oneisopropyl group. In yet other embodiments, the 5-membered ring issubstituted with at least one tent-butyl group.

In certain embodiments, the 1- or 3-position of the 5-membered ring issubstituted with at least one R selected from the group consisting ofalkyl and substituted alkyl. In other embodiments, the 1- or 3-positionof the 5-membered ring is substituted with a methyl group. In yet otherembodiments, the 1- or 3-position of the 5-membered ring is substitutedwith an isopropyl group. In yet other embodiments, the 1- or 3-positionof the 5-membered ring is substituted with a tent-butyl group.

In certain embodiments, the 2-position of the 5-membered ring issubstituted with at least one R selected from the group consisting ofalkyl and substituted alkyl. In other embodiments, the 2-position of the5-membered ring is substituted with a methyl group. In yet otherembodiments, the 2-position of the 5-membered ring is substituted withan isopropyl group. In yet other embodiments, the 2-position of the5-membered ring is substituted with a tent-butyl group.

In certain embodiments, each occurrence of Z is independently selectedfrom the group consisting of CH and CR, so the precatalyst of formula(II) is a substituted indenyl complex.

In certain embodiments, n is 1. In other embodiments, n is 2. In yetother embodiments, n is 3. In yet other embodiments, n is 4.

One of ordinary skill in the art will contemplate from formula (I) andformula (II) that a R can be a substituent on the six-membered ringand/or the five-membered ring, at any proper position. For example, whenthe coordination ligand is indene, as depicted in formula (III), a R canbe a substituent on positions 1, 2, 3, 4, 5, 6, and/or 7. In certainembodiments, a R is attached to the 1- or 3-position of thefive-membered ring. In other embodiments, a R is attached to the2-position of the five-membered ring.

The precatalysts of the invention may possess one or more stereocenters,and each stereocenter may exist independently in either the (R) or (5)configuration. In certain embodiments, precatalysts described herein arepresent in optically active or racemic forms. The precatalysts describedherein encompass racemic, optically-active, regioisomeric andstereoisomeric forms, or combinations thereof that possess thetherapeutically useful properties described herein. Preparation ofoptically active forms is achieved in any suitable manner, including byway of non-limiting example, by resolution of the racemic form withrecrystallization techniques, synthesis from optically-active startingmaterials, chiral synthesis, or chromatographic separation using achiral stationary phase.

In certain embodiments, the precatalysts of the invention exist astautomers. All tautomers are included within the scope of theprecatalysts recited herein.

Compounds described herein also include isotopically-labeled compoundswherein one or more atoms is replaced by an atom having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes suitablefor inclusion in the compounds described herein include and are notlimited to 2_(H,) 3H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N,¹⁵O, ¹⁷O, ¹⁸O, ³²P, and ³⁵S. In certain embodiments, substitution withheavier isotopes such as deuterium affords greater chemical stability.Isotopically-labeled compounds are prepared by any suitable method or byprocesses using an appropriate isotopically-labeled reagent in place ofthe non-labeled reagent otherwise employed.

In certain embodiments, the precatalysts described herein are labeled byother means, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Synthesis

The precatalysts described herein, and other related precatalysts havingdifferent substituents are synthesized using techniques and materialsdescribed herein and as described, for example, in Fieser & Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey & Sundberg, Advanced OrganicChemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts,Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all ofwhich are incorporated by reference for such disclosure).

Precatalysts described herein are synthesized using any suitableprocedures starting from compounds that are available from commercialsources, or are prepared using procedures described herein.Modifications of these procedures are known to those skilled in the art.The scheme included herein are intended to illustrate but not limit thechemistry and methodologies that one skilled in the art may use to makeprecatalysts of the invention.

In certain embodiments, the synthesis of the precatalyst of formula (I)is conducted in one step and can be performed under aerobic conditions,without the use of air sensitive reagents.

In certain embodiments, a transition metal salt (such as, but notlimited to, a halide, triflate, mesylate or tosylate is reacted with analkaline or alkaline-earth salt to yield a mixed salt, such as but notlimited to Na₂PdCl₄. The mixed salt may be reacted with a substitutedindene and a base (such as, but not limited to, cesium, potassium orsodium carbonate in an organic solvent (such as, but not limited to,methanol, ethanol, isopropanol, tetrahydrofuran, and/or 1,4-dioxane. Themixture is stirred at a temperature ranging from about −20° C. to about80° C. In certain embodiments, the precatalyst precipitates out ofsolution, and is isolated and optionally purified by washing,recrystallization and/or extraction. In other embodiments, theprecatalyst is isolated from solution using a method such aschromatography, precipitation, crystallization and/or extraction.

In certain embodiments, the synthesis of the precatalyst of formula (II)comprises reacting a precatalyst of formula (I) with an appropriateligand L, such as but not limited to IPr(1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene), inan organic solvent such as, but not limited to, diethyl ether,tetrahydrofuran, and/or 1,4-dioxane.

Methods

The precatalyst of formula (I) or formula (II) can be used in couplingreactions to promote formation of a carbon-carbon, carbon-oxygen,carbon-nitrogen, and/or carbon-sulfur bond(s). In certain embodiments,the precatalyst of formula (I) or formula (II) can be used to promotethe reactions depicted in FIG. 2.

In certain embodiments, the precatalyst of formula (I) or formula (II)is used to promote the coupling of an aromatic or heteroaromatic boronicacid or ester with an aromatic or heteroaromatic halide, tosylate,triflate, mesylate, sulfamate or carbamate (Suzuki-Miyaura reaction).

In certain embodiments, the precatalyst of formula (I) or formula (II)is used to promote the coupling of an aromatic or heteroaromatic aminewith an aromatic, heteroaromatic or vinylic halide, tosylate, triflate,mesylate, sulfamate or carbamate (Buchwald-Hartwig reaction).

In certain embodiments, the precatalyst of formula (I) or formula (II)is used to promote the coupling of an aromatic or heteroaromatic zinchalide with an aromatic, heteroaromatic or vinylic halide, tosylate,triflate, mesylate, sulfamate or carbamate (Negishi reaction).

In certain embodiments, the precatalyst of formula (I) or formula (II)is used to promote the coupling of an aromatic or heteroaromaticmagnesium halide with an aromatic, heteroaromatic or vinylic halide,tosylate, triflate, mesylate, sulfamate or carbamate (Kumada reaction).

In certain embodiments, the precatalyst of formula (I) or formula (II)is used to promote the coupling of an aromatic or heteroaromatic tinhalide with an aromatic, heteroaromatic or vinylic halide, tosylate,triflate, mesylate, sulfamate or carbamate (Stille reaction).

In certain embodiments, the precatalyst of formula (I) or formula (II)is used to promote the a-arylation of a ketone, aldehyde, imine, amideor ester with an aromatic, heteroaromatic or vinylic halide, tosylate,triflate, mesylate, sulfamate or carbamate (a-arylation reaction).

In certain embodiments, the precatalyst of formula (I) or formula (II)is used to promote the reaction of an alcohol or thiol with an aromatic,heteroaromatic or vinylic halide, tosylate, triflate, mesylate,sulfamate or carbamate (C—S or C—O bond formation).

In certain embodiments, the precatalyst of formula (I) or formula (II)is used to promote the reaction of an aromatic or heteroaromaticsilanol, siloxane or silane with an aromatic, heteroaromatic or vinylichalide, tosylate, triflate or mesylate (Hiyama coupling).

In certain embodiments, the precatalyst of formula (I) or formula (II)is used to promote the anaerobic oxidation of a primary or secondaryalcohol.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that, wherever values and ranges are providedherein, the description in range format is merely for convenience andbrevity and should not be construed as an inflexible limitation on thescope of the invention. Accordingly, all values and ranges encompassedby these values and ranges are meant to be encompassed within the scopeof the present invention. Moreover, all values that fall within theseranges, as well as the upper or lower limits of a range of values, arealso contemplated by the present application. The description of a rangeshould be considered to have specifically disclosed all the possiblesub-ranges as well as individual numerical values within that range and,when appropriate, partial integers of the numerical values withinranges. For example, description of a range such as from 1 to 6 shouldbe considered to have specifically disclosed sub-ranges such as from 1to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6,and so on, as well as individual numbers within that range, for example,1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadthof the range.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXAMPLES

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only, andthe invention is not limited to these Examples, but rather encompassesall variations that are evident as a result of the teachings providedherein.

Materials & Methods: Materials:

Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without purification.

Pentane, THF, diethyl ether and toluene were dried by passage through acolumn of activated alumina followed by storage under dinitrogen. Allcommercial chemicals were used as received except where noted. MeOH (J.T. Baker), ^(i)PrOH (Macron Fine Chemicals), and 200 proof EtOH (DeconLaboratories Inc.) were not dried, but were degassed by sparging withdinitrogen for 1 hour and stored under dinitrogen. Ethyl acetate (FisherScientific) and hexanes (Macron Fine Chemicals) were used as received.Potassium tert-butoxide (99.99%, sublimed), naphthalene (99%),4-chlorotoluene (98%) and 4-chloroanisole (99%) were purchased fromAldrich. 2,6-dimethylboronic acid (98%), 1-naphthaleneboronic acid(97%), 1-chloronaphthalene (90+%) and 2-methoxyboronic acid (97%) werepurchased from Fisher Scientific. Potassium carbonate was purchased fromMallinckrodt. 1,3-divinyltetramethyldisiloxane and 4-methylbiphenyl werepurchased from TCI. Phenylboronic acid (98%) and2,4,6-trimethylbenzeneboronic acid (97%) were purchased from Alfa Aesar.Potassium carbonate was ground up with a mortar and pestle and stored inan oven at 130° C. prior to use. 4-chlorotoluene, 2-chloro-m-xylene,1-chloronaphthalene, 4-chloroanisole and1,3-divinyltetramethyldisiloxane were degassed prior to use throughthree freeze-pump-thaw cycles.

Deuterated solvents were obtained from Cambridge Isotope Laboratories.C₆D₆ was dried over sodium metal and stored under nitrogen, whiled₄-MeOH, d₈-^(i)PrOH, and d₈-THF were not dried but were degassed priorto use through three freeze-pump-thaw cycles.

Literature procedures were used to prepare the following compounds: IPr(Arduengo, et al., 1999, Tetrahedron 55:14523; Tang, et al., 2011, J.Am. Chem. Soc. 133:11482), (η³-allyl)Pd(IPr)(Cl) (1-IPr) (Viciu, et al.,2002, Org. Lett. 4:4053) and (72 ³-cinnamyl)Pd(IPr)(Cl) (2-IPr) (Marion,et al., 2006, J. Am. Chem. Soc. 128:4101).

Methods:

Experiments were performed under a dinitrogen atmosphere in an M-Braundry box or using standard Schlenk techniques unless otherwise stated.Under standard glovebox conditions purging was not performed betweenuses of pentane, benzene and toluene; thus when any of these solventswere used, traces of all these solvents were in the atmosphere and couldbe found intermixed in the solvent bottles. Moisture- and air-sensitiveliquids were transferred by stainless steel cannula on a Schlenk line orin a dry box.

Flash chromatography was performed on silica gel 60 (230-400 mesh,Fisher Scientific).

NMR spectra were recorded on Agilent-400, -500 and -600 spectrometersand Varian-300, -500 spectrometers at ambient probe temperatures unlessnoted. For variable temperature NMR, the sample temperature wascalibrated by measuring the distance between the OH and CH₂ resonancesin ethylene glycol (99%, Aldrich). Chemical shifts are reported withrespect to residual internal protio solvent for ¹H and ¹³C{¹H} NMRspectra.

Gas chromatography analyses (GC) were performed on a Shimadzu GC-2010Plus apparatus equipped with a flame ionization detector and a ShimadzuSHRXI-5MS column (30 m, 250 μm inner diameter, film: 0.25 μm). Thefollowing conditions were utilized for GC analyses: flow rate 1.23mL/min constant flow, column temperature 50° C. (held for 5 min), 20°C./min increase to 300° C. (held for 5 min), total time 22.5 min.

High resolution mass spectrometry was performed using an ion-cyclotronresonance (ICR) mass spectrometer equipped with a superconducting (7T)magnet.

X-Ray Crystallography:

X-ray diffraction experiments were carried out on either a RigakuMercury 275R CCD (SCX mini) diffractometer using graphite-monochromatedMo Kα radiation (λ=0.71073 Å) at −50° C. or a Rigaku MicroMax-007HFdiffractometer coupled to a Saturn994+ CCD detector with Cu Kα radiation(λ=1.54178Å) at −180° C. The crystals were mounted on MiTeGen polyimideloops with immersion oil. The data frames were processed using RigakuCrystalClear and corrected for Lorentz and polarization effects. UsingOlex2, the structure was solved with the XS structure solution programusing direct methods and refined with the XL refinement package usingleast squares minimisation. The non-hydrogen atoms were refinedanisotropically. Hydrogen atoms were refined using the riding model.

Example 1 Synthesis and Characterization Synthetic Procedures for1-Substituted Indenes:

1-Methylindene:

Lithium indenyl (1.00 g, 8.25 mmol) was added to a 100 mL Schlenk flaskin a glovebox and dissolved in 50 mL of diethyl ether. Methyl iodide(0.62 mL, 9.9 mmol) was added to the Schlenk flask via syringe. Thereaction mixture was stirred for two hours at room temperature. Afterthis time, the mixture was poured into a separatory funnel and washedthree times with water. The organic layer was dried over MgSO₄,filtered, and the volatiles removed under reduced pressure to yield theproduct as a pale yellow oil. Yield: 0.70 g, 65%. ¹H NMR data wasconsistent with that previously reported in Villaseñor, et al., 2013,Eur. J. Inorg. Chem. 2013:1184-1196.

1-iso-Propylindene:

This compound was synthesized using the procedure reported by Someya, etal., 2010, Tetrahedron 66:5993-5999.

1-Tert-Butylindene:

Lithium indenyl (20.0 g, 0.164 mol) was added to a 500 mL Schlenk flaskin a glovebox and 200 mL of diethyl ether was added to dissolve thecomplex. Silver bromide (0.3 g, 1.59 mmol) was added to the solution;the flask was removed from the glovebox and stirred in a −78° C. bath.Upon cooling, a yellow precipitate appeared (lithium indenyl is notsoluble in diethyl ether at this temperature). 2-bromo-2-methylpropane(22.1 mL, 0.18 mol) was added slowly via syringe. The reaction mixturewas warmed to room temperature and stirred for 12 hours. A homogenoussolution resulted upon warming to room temperature. After this time, theflask was opened to air and the product was extracted into 300 mL ofethyl acetate and washed with an aqueous solution of ammonium chloride.The aqueous layer was extracted twice (2× 200 mL) with ethyl acetate.The organic layers were combined, dried over MgSO₄, filtered and thevolatiles were removed. The resulting oil was dissolved in hexanes andpassed through a pad of silica gel. The solvent was removed via rotaryevaporator to yield a yellow oil. Yield: 22.7 g, 80%. ¹M NMR data wasconsistent with that previously reported in Someya, et al., 2010,Tetrahedron 66:5993-5999.

Synthetic Procedures for Complexes:

(η³-indenyl)₂(μ-Cl)₂Pd₂(3a):

PdCl₂ (1.00 g, 5.64 mmol) and NaCl (0.658 g, 11.3 mmol) were added to a250 mL round bottom flask. MeOH (70 mL) was added and the reactionmixture heated at 50° C. for 30 minutes, at which time it becamehomogeneous. The solution was allowed to cool to room temperature.Indene (0.650 g, 5.64 mmol) was added, followed by Na₂CO₃ (0.888 g, 8.46mmol) and the reaction stirred for 2 hours at room temperature. Thereaction mixture was filtered and the resulting brown solid washed withwater and diethyl ether. The product was dried under vacuum to yield 3aas a brown solid. Yield: 1.22 g, 84%. The ¹H NMR data was consistentwith that published in the literature (Sui-Seng, et al., 2004,Organomet. 23:1236)

(η³-1-Me-indenyl)₂(μ-Cl)₂Pd₂(3b):

PdCl₂ (0.885 g, 5.0 mmol) and NaCl (0.585 g, 10.0 mmol) were added to a100 mL round bottom flask. MeOH (50 mL) was added and the reactionmixture heated at 50° C. for 30 minutes, at which time it becamehomogeneous. The solution was allowed to cool to room temperature.1-Methyl-indene (0.650 g, 5.00 mmol) was added, followed by Na₂CO₃ (1.06g, 10.0 mmol) and the reaction stirred for 2 hours at room temperature.The reaction mixture was filtered and the resulting brown solid washedwith water and diethyl ether. The product was dried under vacuum toyield 3b as a brown solid. Yield: 1.20 g, 89%.

¹HNMR (CDCl₃, 600 MHz): 6.77-6.85 (m, C₆H₄, 8H), 6.64 (br, MeC₅H₂, 2H),5.66 (br, MeC₅H₂, 2H), 1.16 (s, Me-Ind, 6H). ¹³C{¹H} NMR (CDCl₃, 150MHz): 141.9, 140.7, 128.2, 127.7, 118.3, 117.1, 110.0, 96.2, 74.8, 13.5.

(η³-1-^(i)Pr-indenyl)₂(μ-Cl)₂Pd₂(3c):

PdCl₂ (0.337 g, 1.89 mmol) and NaCl (0.220 g, 3.78 mmol) were added to a100 mL round bottom flask. MeOH (30 mL) was added and the reactionmixture heated at 50° C. for 30 minutes, at which time it becamehomogeneous. The solution was allowed to cool to room temperature.1-Isopropyl-indene (0.300 g, 1.89 mmol) was added, followed by Na₂CO₃(0.300 g, 2.84 mmol) and the reaction was for 2 hours at roomtemperature. The reaction mixture was filtered and the resulting brownsolid washed with water and diethyl ether. The product was dried undervacuum to yield 3c as a brown solid. Yield: 0.400 g, 71%.

¹H NMR (CDCl₃, 600 MHz): 6.75-6.90 (m, C₆H₄, 8H), 6.58 (br, ^(i)PrC₅H₂,2H), 5.64 (br, ^(i)PrC₅H₂, 2H), 2.11 (sept, J=6.7 Hz, (CH₃)₂CH, 2H),1.21 (d, J=6.9 Hz, (CH₃)₂CH, 6H), 1.18 (d, J=6.9 Hz, (CH₃)₂CH, 6H).¹³C{¹H} NMR (CDCl₃, 150 MHz): 140.9, 140.7, 128.0, 127.6, 118.5, 117.7,117.6, 105.6, 75.2, 27.0, 20.6, 20.3.

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂(3d):

PdCl₂ (0.412 g, 2.32 mmol) and NaCl (0.269 g, 4.64 mmol) were added to a100 mL round bottom flask. MeOH (40 mL) was added and the reactionmixture heated at 50° C. for 30 minutes, at which time it becamehomogeneous. The solution was allowed to cool to room temperature.1-t-Butyl-indene (0.400 g, 2.32 mmol) was added, followed by Na₂CO₃(0.369 g, 3.48 mmol) and the reaction stirred for 2 hours at roomtemperature. The reaction mixture was filtered and the resulting brownsolid washed with water and diethyl ether. The product was dried undervacuum to yield 3d as a brown solid. Yield: 0.550 g, 77%.

¹H NMR (CDCl₃, 600 MHz): 7.11 (br, ^(t)BuC₅H₂, 2H), 6.65-6.80 (m, C₆H₄,8H), 5.50 (d, J=2.7 Hz, ^(t)BuC₅H₂, 2H), 1.29 (s, (CH₃)₃C, 18H). ¹³C{¹H}NMR (CDCl₃, 150 MHz): 142.1, 140.9, 127.7, 127.4, 120.3, 120.2, 118.9,118.8, 107.7, 107.6, 73.4, 34.4, 28.9.

(η³-indenyl)Pd(IPr)(Cl) (4a-IPr):

(η³-indenyl)₂(μ-Cl)₂Pd₂ (3a) (0.600 g, 1.17 mmol) and IPr (0.900 g, 2.34mmol) were added to a 100 mL Schlenk flask. Diethyl ether (40 mL) wasadded to the flask via cannula. The resulting solution was stirred for90 minutes, during which time the reaction mixture became homogeneous.The solution was passed through a pad of silica gel, followed by theremoval of solvent using a rotary evaporator to give 4a-IPr as an orangepowder. Yield: 1.33 g, 88%. The ¹H NMR data was consistent with thatpublished in the literature (Bielinski, et al., 2013, Organomet.32:4025).

(η³-1-Me-indenyl)Pd(IPr)(Cl) (4b-IPr):

(72 ³-1-Me-indenyl)₂(μ-Cl)₂Pd₂ (3b) (0.300 g, 0.502 mmol) and IPr (0.390g, 1.00 mmol) were added to a 100 mL Schlenk flask. Diethyl ether (30mL) was added to the flask via cannula. The resulting solution wasstirred for 90 minutes, during which time the reaction mixture becamehomogeneous. The solution was passed through a pad of silica gel,followed by the removal of solvent using a rotary evaporator to give4b-IPr as an orange powder. Yield: 0.550 g, 81%. X-ray quality crystalswere grown by slow evaporation from a saturated pentane solution.

¹H NMR (C₆D₆, 600 MHz): 7.22 (t J=7.6 Hz, 2H, para-H Ar_(IPr)), 7.11 (d,J=6.5 Hz, 2H, meta -H Ar_(IPr)), 7.07 (d, J=7.3 Hz, 2H, meta-HAr_(IPr)), 6.81 (t, J=8.0 Hz, 1H, Ind), 6.77 (t, J=7.7 Hz, 1H, Ind),6.41 (t, J=8.1 Hz, 1H, Ind), 6.03 (br, 1H, Ind) 5.87 (d, J=7.1 Hz, 1H,Ind), 5.21 (br, 1H, Ind), 3.39 (sept, J=6.8 Hz, 2H, (CH₃)₂CH), 2.83(sept, J=6.8 Hz, 2H, (CH₃)₂CH), 1.58 (s, 3H, CH₃-Ind), 1.48 (d, J=6.6Hz, 6H, (CH₃)₂CH), 1.19 (d, J=6.6 Hz, 6H, (CH₃)₂CH), 1.06 (d, J=6.7 Hz,6H, (CH₃)₂CH), 0.93 (d, J=6.7 Hz, 6H, (CH₃)₂CH). ¹³C{¹H} NMR (C₆D₆, 150MHz): 179.9, 146.6, 140.0, 138.4, 137.1, 130.5, 125.5, 124.9, 124.8,124.6, 117.0, 116.1, 110.1, 101.0, 66.1, 29.1, 29.0, 26.7, 26.0, 24.1,22.9, 12.4. Anal. Calcd for C₃₇H₄₅ClN₂Pd: C, 67.37; H, 6.88; N, 4.25.Found: C, 67.15; H, 7.00; N, 4.27.

(η³-1-^(i)Pr-indenyl)Pd(IPr)(Cl) (4c-IPr):

(η³-1-^(i)Pr-indenyl)₂(μ-Cl)₂Pd₂ (3c) (0.300 g, 0.502 mmol) and IPr(0.390 g, 1.00 mmol) were added to a 100 mL Schlenk flask. Diethyl ether(30 mL) was added to the flask via cannula. The resulting solution wasstirred for 90 minutes, during which time the reaction mixture becamehomogeneous. The solution was passed through a pad of silica gel,followed by the removal of solvent using a rotary evaporator to give4c-IPr as an orange powder. Yield: 0.550 g, 81%. X-ray quality crystalswere grown by slow evaporation from a saturated pentane solution.

¹H NMR (C₆D₆, 600 MHz): 7.25 (t, J=7.7 Hz, 2H, para-H Ar_(IPr)), 7.15(obscured by solvent, 2H, meta-H Ar_(IPr)), 7.09 (dd, J=1.4, 6.3 Hz, 2H,meta-H Ar_(IPr)), 6.89 (d, J=7.4 Hz, 1H, Ind), 6.83 (t, J=8.4 Hz, 1H,Ind), 6.55 (s, 2H, HCCH), 6.42 (t, J=7.4 Hz, 1H, Ind), 6.05 (d, J=2.7Hz, 1H, Ind), 5.89 (d, J=7.4 Hz, 1H, Ind), 5.29 (d, J=2.8Hz, 1H, Ind)3.36 (sept, J=6.8 Hz, 2H, (CH₃)₂CH), 2.86 (sept, J=6.8 Hz, 1H,(CH₃)₂CH-Ind), 2.82 (sept, J=6.8 Hz, 2H, (CH₃)₂CH), 1.48 (d, J=6.7 Hz,2H, (CH₃)₂CH), 1.19 (d, J=6.9 Hz, 6H, (CH₃)₂CH), 1.18 (d, J=5.2 Hz, 3H,(CH₃)₂CH-Ind), 1.16 (d, J=4.5 Hz, 3H, (CH₃)₂CH-Ind), 1.06 (d, J=6.8 Hz,6H, (CH₃)₂CH), 0.93 (d, J=6.8 Hz, 6H, (CH₃)₂CH). ¹³C{¹H} NMR (C₆D₆, 150MHz): 179.6, 146.8, 146.7, 138.1, 137.2, 137.0, 130.3, 125.1, 125.0,124.8, 124.6, 124.5, 117.4, 116.5, 110.5, 105.2, 67.4, 29.2, 29.1, 26.8,26.0, 24.1, 22.9, 22.1, 21.0. Anal. Calcd for C₃₉H₄₉ClN₂Pd: C, 68.11; H,7.18; N, 4.07. Found: C, 67.89; H, 7.42; N, 4.04.

(η³-1-^(t)Bu-indenyl)Pd(IPr)(Cl) (4d-IPr):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.400 g, 0.65 mmol) and IPr(0.505 g, 1.30 mmol) were added to a 100 mL Schlenk flask. Diethyl ether(40 mL) was added to the flask via cannula. The resulting solution wasstirred for 90 minutes, during which time the reaction mixture becamehomogeneous. The solution was passed through a pad of silica gel,followed by the removal of solvent using a rotary evaporator to give4d-IPr as an orange powder. Yield: 0.705 g, 78%. X-ray quality crystalswere grown by slow evaporation from a saturated pentane solution.

¹H NMR (C₆D₆, 600 MHz): 7.27 (d, J=6.9 Hz, 1H, Ind), 7.26 (t, J=7.4 Hz,2H, para-H Ar_(IP r)),7.15 (obscured by solvent, 2H, meta-H Ar_(IPr))7.09 (d, J=7.6 Hz, 2H, meta-H Ar_(IPr)), 6.83 (t, J=7.5 Hz, 1H, Ind),6.54 (s, 2H, HCCH), 6.44 (t, J=7.5 Hz, 1H, Ind), 6.19 (d, J=2.9 Hz, 1H,Ind), 5.83 (d, J=7.4 Hz, 1H, Ind), 5.12 (d, J=2.9 Hz, 1H, Ind), 3.42(sept, J=6.7 Hz, 2H, (CH₃)₂CH), 2.83 (sept, J=6.7 Hz, 2H, (CH₃)₂CH),1.47 (d, J=6.7 Hz, 6H, (CH₃)₂CH), 1.45 (s, 9H, (CH₃)₃C), 1.18 (d, J=6.7Hz, 6H, (CH₃)₂CH), 1.05 (d, J=6.7 Hz, 6H, (CH₃)₂CH), 0.92 (d, J=6.7 Hz,6H, (CH₃)₂CH). ¹³C{¹H} NMR (C₆D₆, 150 MHz): 178.5, 146.8, 146.7, 139.5,139.0, 137.1, 130.3, 124.9, 124.8, 124.7, 124.5, 119.7, 117.2, 115.9,107.5, 64.3, 34.6, 30.2, 29.2, 29.1, 26.9, 26.0, 24.1, 22.9, 1.8.

(μu-indenyl)(μ-Cl)Pd₂(IPr)₂ (7-IPr):

(η³-indenyl)Pd(IPr)(Cl) (4a-IPr) (0.200 g, 0.31 mmol) and K₂CO₃ (0.086g, 0.62 mmol) were added to a 100 mL Schlenk flask. Degassed MeOH (30mL) was added to the flask via cannula. The reaction mixture was stirredat room temperature for 2 hours. The precipitate was filtered in air andwashed with water to remove excess salts. The solid was washed withpentane and dried under vacuum to give 7-IPr as a dark yellow solid.Yield: 0.150 g, 85%. X-ray quality crystals were grown from a saturatedtoluene solution layered with pentane (V(toluene):V(pentane) =1:2) at-35° C.

¹H NMR (C₆D₆, 400 MHz): 7.25 (t, J=7.7 Hz, 4H, para-H Ar_(IPr)),7.08-7.14 (m, 8H, meta-H Ar_(IPr)), 6.71 (dd, J=2.2 Hz, 2H, Ind), 6.64(s, 4H, HCCH), 6.37 (dd, J=2.1 Hz, 2H, Ind), 4.87 (d, J=3.9 Hz, 2H,Ind), 3.18 (sept, J=6.9 Hz, 4H, (CH₃)₂CH), 3.11 (sept, J=6.9 Hz, 4H,(CH₃)₂CH), 3.00 (t, J=3.9 Hz, 1H, Ind) 1.33 (d, J=6.8 Hz, 12H, (CH₃)₂CH)1.14 (d, J=5.8 Hz, 12H, (CH₃)₂CH) 1.11 (d, J=6.6 Hz, 12H, (CH₃)₂CH) 1.09(d, J=6.9 Hz, 12H, (CH₃)₂CH). ¹³C{¹H} NMR (C₆D₆, 100 MHz): 188.8, 147.2,146.8, 146.3, 137.8, 129.7, 124.5, 124.3, 123.4, 122.5, 121.9, 68.6,45.5, 29.2, 29.1, 26.4, 25.9, 24.0, 23.9. Anal. Calcd for C₆₃H₇₉ClN₄Pd₂:C, 66.34; H, 6.98; N, 4.91. Found: C, 66.59; H, 7.03; N, 4.82.

(η³-1-^(t)Bu-indenyl)PdaPr*^(OMe))(Cl) (4d-IPr*^(OMe)):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.165 g, 0.265 mmol) andIPr*^(OMe) (0.500 g, 0.53 mmol) were added to a 100 mL Schlenk flask andplaced under an atmosphere of nitrogen. THF (30 mL) was added to theflask via cannula. The resulting solution was stirred for 24 hours,during which time the reaction mixture became homogeneous. The reactionmixture was passed through a pad of silica gel with celite on top.Approximately 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A beige solid wascollected via vacuum filtration. Yield: 0.534 g, 80%.

¹H NMR (C₆D₆, 600 MHz): 7.65 (d, J=5.75 Hz, 4H), 7.47 (d, J =7.67 Hz,1H), 7.32 (d, J=7.47 Hz, 4H), 7.22 (t, J=7.57 Hz, 4H), 7.13 (t, J=7.44Hz, 3H), 7.03-6.98 (m, 6H), 6.94 (d, J=2.70 Hz, 2H), 6.91-6.82 (m, 14H),6.78-6.75 (m, 2H), 6.69 (s, 2H), 6.66-6.63 (m, 3H), 6.20 (t, J=7.46 Hz,1H), 6.00 (s, 2H), 5.88 (d, J=7.40 Hz, 1H), 5.47 (d, J=2.19 Hz, 1H),5.13 (s, 2H), 3.15 (s, 6H), 1.65 (s, 9H) ppm. ¹³C{¹H} NMR (C₆D₆ 150MHz): 159.93, 144.94, 144.39, 131.34, 131.20, 130.08, 129.88, 128.68,128.50, 128.30, 128.11, 127.13, 126.89, 126.85, 124.45, 115.74, 115.36,109.06, 54.69, 52.13, 34.85, 29.96 ppm.

(η³-1-^(t)Bu-indenyl)Pd(XPhos)(Cl) (4d-XPhos):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and XPhos(0.460 g, 0.98 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solidwas collected via vacuum filtration. Yield: 0.650 g, 86%.

¹H NMR (CDCl₃, 600 MHz): 7.98-7.93 (m, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.34(m, 2H), 7.06-7.02 (m, 4H), 6.89-6.83 (m, 2H), 6.42 (s, 1H), 4.79 (s,1H), 2.94 (sept, J=6.5 Hz, 1H), 2.70 (sept, J=6.6 Hz, 1H), 2.52 (sept,J=6.6 Hz, 1H), 2.22 (d, J=11.1 Hz, 1H), 2.03 (d, J=12.6 Hz, 1H),1.57-1.37 (m, 21H), 1.32-1.26 (m, 14H), 0.99-0.92 (t, J=7.2 Hz, 12H)ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): 133.78, 128.49, 126.16, 124.76,121.28, 120.84, 34.62, 31.04, 30.89, 30.00, 29.96, 29.25, 26.16, 24.34,24.31, 23.01, 22.57 ppm. ³¹P{¹H} NMR (CDCl₃, 121 MHz): 59.68 ppm. Anal.Calcd for C₄₆H₆₄ClPdP: C, 69.95; H, 8.17; N, 0.00. Found: C, 69.61; H,8.52; N, less than 0.02.

(η³-1-^(t)Bu-indenyl)Pd(RuPhos)(Cl) (4d-RuPhos):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and RuPhos(0.448 g, 0.98 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solidwas collected via vacuum filtration. Yield: 0.694 g, 89%.

¹H NMR (CDCl₃, 600 MHz): 7.65-7.61 (m, 1H), 7.43-7.36 (m, 2H), 7.26(obscured by solvent, 1H), 7.01 (t, J=7.5 Hz, 1H), 6.89 (d, J=7.4 Hz,1H), 6.83 (t, J=7.4 Hz, 1H), 6.66-6.58 (m, 4H), 6.40 (s, 1H), 4.66 (d,J=2.5 Hz, 1H), 4.52-4.44 (sept, J=6.1 Hz, 2H), 2.23 (m, 1H), 2.09 (m,1H), 2.05-1.99 (m, 2H), 1.69-1.62 (m, 5H), 1.56 (s, 9H), 1.49-1.43 (m,5H), 1.33-1.19 (m, 9H), 1.16-0.92 (m, 11H), 0.54 (d, J=12.2 Hz, 2H) ppm.¹³C{¹H} NMR (CDCl₃, 150 MHz): 157.25, 139.13, 137.57, 137.40, 133.08,129.40, 128.82, 126.03, 125.66, 124.14, 120.81, 118.88, 106.47, 71.42,71.06, 34.54, 34.51, 30.02, 29.98, 27.55, 27.44, 26.31, 22.51, 22.45,22.42 ppm. ³¹P{¹H} NMR (CDCl₃, 121 MHz): 57.13 ppm. Anal. Calcd forC₄₃H₅₈ClPdPO₂: C, 66.23; H, 7.50; N, 0.00. Found: C, 66.00; H, 7.48; N,less than 0.02.

(η³-1-^(t)Bu-indenyl)Pd(SPhos)(Cl) (4d-SPhos):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and SPhos(0.395 g, 0.98 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solidwas collected via vacuum filtration.

Yield: 0.622 g, 86%.

¹H NMR (CDCl₃, 600 MHz): 7.73-7.68 (m, 1H), 7.45-7.42 (m, 2H), 7.41 (d,J=7.7 Hz, 1H), 7.37 (t, J=8.4 Hz, 1H), 7.03-6.97 (m, 2H), 6.79 (t, J=7.4Hz, 1H), 6.79-6.62 (m, 3H), 6.44 (d, J=1.7 Hz, 1H), 4.39 (d, J=2.6 Hz,1H), 3.76 (s, 3H), 3.68 (s, 3H), 2.13-1.98 (m, 4H), 1.74-1.69 (m, 2H),1.57 (s, 9H), 1.54-1.51 (m, 6H), 1.44-1.42 (m, 2H), 1.36-1.20 (m, 5H),1.11-0.96 (m, 3H) ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): 138.44, 133.06,129.78, 126.12, 124.23, 120.77, 118.91, 104.01, 103.77, 69.23, 55.62,29.95, 29.34, 28.46, 27.29, 26.28, 25.96 ppm. ³¹P{¹H} NMR (CDCl₃, 121MHz): 57.50 ppm. Anal. Calcd for C₃₉H₅₀ClPdPO₂: C, 64.73; H, 6.96; N,0.00. Found: C, 66.63; H, 6.80; N, less than 0.02.

(η³-1-^(t)Bu-indenyl)Pd(P{^(t)Bu}₃)(Cl) (4d-P^(t)Bu₃):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and P^(t)Bu₃(0.448 g, 0.98 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solidwas collected via vacuum filtration. Yield: 0.694 g, 89%.

¹HNMR (CDCl₃, 600 MHz): 7.44 (d, J=7.74 Hz, 1H), 7.00-6.95 (m, 2H),6.81-6.78 (m, 1H), 6.40 (d, J=2.64, 1H), 5.75 (s, 1H), 2.15 (s, 36H).¹³C{¹H} NMR (CDCl₃, 150 MHz): 139.81, 127.24, 124.93, 121.14, 118.68,107.03, 70.28, 40.65, 35.87, 33.18, 29.61 ppm. ³¹P{¹H} NMR (CDCl₃, 121MHz): 99.95. Anal. Calcd for C₂₅H₄₀C1PdP: C, 58.48; H, 7.85; N, 0.00.Found: C, 58.59; H, 7.69; N, less than 0.02.

(η³-1-^(t)Bu-indenyl)Pd(PCy₃)(Cl) (4d-PCy₃):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and PCy₃(0.269 g, 0.96 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solidwas collected via vacuum filtration. Yield: 0.546 g, 92%.

¹HNMR (CDCl₃, 600 MHz): 7.44 (d, J=7.75 Hz, 1H), 6.98 (t, J=7.53 Hz,1H), 6.93 (d, J=7.39 Hz, 1H), 6.83 (t, J=7.45 Hz, 1H), 6.49 (d, J=2.56Hz, 1H), 4.98 (d, J=2.66 Hz, 1H), 2.12-2.05 (m, 3H), 1.92-1.89 (m, 3H),1.74-1.76 (m, 9H), 1.70-1.67 (m, 3H), 1.55 (s, 9H), 1.31-1.17 (m, 15H)ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): 139.21, 138.07, 125.93, 124.41,120.94, 118.32, 107.82, 64.53, 35.76, 30.31, 29.99, 27.79, 26.57, 22.57,14.29 ppm. ³¹P{¹H} NMR (CDCl₃, 121 MHz): 48.83 ppm. Anal. Calcd forC₃₁H₄₈ClPdP: C, 62.73; H, 8.15; N, 0.00. Found: C, 62.97; H, 8.30; N,less than 0.02.

(η³-1-^(t)Bu-indenyl)Pd(P{o-tol}₃)(Cl) (4d-P(o-tol)₃):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and P(o-tol)₃(0.262 g, 0.96 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solidwas collected via vacuum filtration. Yield: 0.550 g, 89%.

¹H NMR (CDCl₃, 600 MHz): 7.39 (d, J=7.2 Hz, 6H), 7.21 (s, 8 H), 6.95 (t,J=7.46, 1H), 6.72 (s, 1H), 6.57 (s, 1H), 4.74 (s, 1H), 2.02 (s, 9H),1.61 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 150 MHz): 143.42, 139.43, 138.08,132.31, 130.75, 126.52, 126.39, 126.00, 120.62, 117.75, 108.16, 34.99,34.95, 30.12, 30.08, 23.16 ppm. ³¹P{¹H} NMR (CDCl₃, 121 MHz): 32.68 ppm.Anal. Calcd for C₃₄H₃₆ClPdP: C, 66.13; H, 5.88; N, 0.00. Found: C,66.09; H, 5.74; N, less than 0.02.

(η³-1-^(t)Bu-indenyl)Pd(PPh₃)(Cl) (4d-PPh₃):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and PPh₃(0.252 g, 0.96 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solidwas collected via vacuum filtration. Yield: 0.535 g, 93%.

¹H NMR (CDCl₃, 600 MHz): 7.48-7.52 (m, 6H), 7.35-7.43 (m, 10H), 7.03 (t,J=7.62 Hz, 1H), 6.81 (t, J=7.48 Hz, 1H), 6.52 (d, J=2.71 Hz, 1H), 6.21(d, J=7.38 Hz, 1H), 4.15 (d, J=2.83 Hz, 1H), 1.59 (s, 9H) ppm. ¹³C{¹H}NMR (CDCl₃, 150 MHz): 143.85, 137.13, 136.27, 133.97, 132.27, 131.85,130.58, 128.26, 126.15, 125.54, 120.69, 116.47, 107.61, 97.49 ppm.³¹P{¹H} NMR (CDCl₃, 121 MHz): 29.09 ppm. Anal. Calcd for C₃₁H₃₀ClPdP: C,64.71; H, 5.26; N, 0.00. Found: C, 64.44; H, 5.16; N, less than 0.02.

(η³-1-^(t)Bu-indenyl)Pd(DavePhos)(Cl) (4d-DavePhos):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and DavePhos(0.378 g, 0.96 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orangesolid, which contained two isomers in an approximately 1:1 ratio, wascollected via vacuum filtration. Yield: 0.622 g, 88%.

¹H NMR (CDCl₃, 600 MHz): Isomer A: 7.78-7.74 (m, 1H), 7.48-7.40 (m, 3H),7.39-7.34 (m, 2H), 7.19 (d, J=7.52 Hz, 1H), 7.08-6.96 (m, 3H), 6.89-6.85(m, 1H), 6.68 (d, J=7.34 Hz,1H), 6.33 (d, J=2.82 Hz, 1H), 4.45 (d,J=2.66 Hz 1H), 2.55 (s, 6H), 1.54 (s, 9H), 1.22-0.76 (m, 22H) ppm.Isomer B: 7.70-7.66 (m, 1H), 7.48-7.40 (m, 3H), 7.29-7.27 (m, 2H), 7.17(d, J=7.58 Hz, 1H), 7.08-6.96 (m, 3H), 6.84-6.81 (m, 1H), 6.75 (d,J=7.31 Hz, 1H), 6.48 (d, J=2.78 Hz, 1H), 4.55 (d, J=2.71 Hz, 1H), 2.62(s, 6H), 2.29-1.66 (m, 22H), 1.55 (s, 9H) ppm. ¹³C{¹H} NMR (CDCl₃, 150MHz): 150.96, 150.92, 143.95, 143.63, 139.44, 139.28, 138.18, 138.04,137.88, 137.77, 133.77, 133.72, 133.53, 133.48, 132.38, 132.26, 128.96,125.96, 125.89, 125.80, 125.70, 124.16, 123.91, 120.78, 120.71, 120.56,120.25, 118.23, 118.13, 43.96, 43.67, 34.58, 34.48, 34.34, 34.18, 34.13,31.75, 31.73, 31.13, 30.39, 30.17, 29.73, 29.70, 29.14, 29.02, 28.17,27.23, 27.04, 26.93, 26.06, 25.98, 25.78, 25.61 ppm. ³¹P{¹H} NMR (CDCl₃,121 MHz): 58.01, 56.37 ppm. Anal. Calcd for C₃₉H₅₁ClPdPN: C, 66.28; H,7.27; N, 1.98. Found: C, 66.26; H, 7.51; N, 1.86.

(η³-1-^(t)Bu-indenyl)Pd(AmPhos)(Cl) (4d-AmPhos):

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and AmPhos(0.255 g, 0.96 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solidwas collected via vacuum filtration. Yield: 0.526 g, 91%.

¹H NMR (CDCl₃, 600 MHz): 7.53 (t, 2H), 7.44 (d, 1H), 7.01 (t, 1H), 6.92(d, 1H), 6.83 (t, 1H), 6.67 (d, 2H), 6.54 (d, 1H), 4.81 (d, 1H), 3.02(s, 6H), 1.58 (s, 9H), 1.37-1.32 (m, 18H) ppm. ¹³C{¹H} NMR (CDCl₃, 150MHz): 136.85, 136.76, 126.83, 124.44, 120.99, 119.18, 110.55, 110.47,108.43, 108.38, 70.05, 70.02, 40.19, 30.48, 30.44, 30.39, 29.69, 29.65ppm. ³¹P{¹H} NMR (CDCl₃, 121 MHz): 73.34 ppm. Anal. Calcd forC₂₉H₄₃ClPdPN: C, 60.21; H, 7.49; N, 2.42. Found: C, 59.64; H, 7.51; N,2.23.

(η³-1-^(t)Bu-indenyl)Pd(QPhos)(CI) (4d-QPhos):

(72 ³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (3d) (0.300 g, 0.48 mmol) and QPhos(0.682 g, 0.96 mmol) were added to a 100 mL Schlenk flask and placedunder an atmosphere of nitrogen. THF (20 mL) was added to the flask viacannula. The resulting solution was stirred for 60 minutes, during whichtime the reaction mixture became homogeneous. The mixture was opened toair and 90% of the solvent was evaporated under reduced pressure.Pentane was added to precipitate solid from solution. A red-orange solidwas collected via vacuum filtration. Yield: 0.870 g, 85%.

¹H NMR (CDCl₃, 600 MHz): 7.48 (d, 1H), 7.14-7.04 (m, 25H), 6.93 (t, 1H),6.87 (d, 1H), 6.74 (t, 1H), 6.38 (d, 1H), 5.55 (d, 1H), 5.27 (s, 1H),4.66 (s, 1H), 4.51 (d, 2H), 1.56 (s, 9H), 1.22 (d, 9H), 1.02 (d, 9H)ppm. ¹³C{¹H} NMR (CDCl₃, 150 MHz): 135.21, 132.77, 127.49, 126.88,126.75, 125.35, 121.34, 118.85, 87.72, 36.08, 36.04, 31.33, 31.29,30.41, 30.37, 29.56, 29.52 ppm. ³¹P{¹H} NMR (CDCl₃, 121 MHz): 73.68 ppm.Anal. Calcd for C₆₁H₆₂ClPdP: C, 71.56; H, 6.10; N, 0.00. Found: C, 70.36H, 6.30; N, less than 0.02.

(η³-1-^(t)Bu-indenyl)Pd(BrettPhos)(Cl) (4d-BrettPhos):

In a nitrogen filled glovebox, [Pd(1-^(t)Bu-indenyl)Cl]₂ (156.1 mg, 0.25mmol) and BrettPhos (268.1 mg, 0.5 mmol) were added to a 100 mL Schlenkflask equipped with a magnetic stir bar. Anhydrous THF (10 mL) was addedto the flask to yield an immediate red solution. The solution wasstirred for 20 minutes at room temperature, at which time the solventwas removed on a Schlenk line. Upon removal of the solvent, the flaskwas opened to air and the red, viscous oil was dissolved in pentane. Thesolution was passed through a pad of celite, followed by evaporation ofthe pentane using a rotary evaporator. The red solid (0.386 g, 91%) wasused without further purification. X-ray quality crystals were producedby placing a concentrated pentane solution at −10° C.

¹H NMR (Methanol-d₄, 500 MHz): 7.38 (d, J=7.9 Hz, 2H), 7.35 (t, J=7.2Hz, 1H), 7.26 (s, 1H), 7.19 (dd, J=5.6, 3.2 Hz, 1H), 7.14 (d, J=9.0 Hz,1H), 7.05 (t, J=7.3 Hz, 1H), 6.96 (s, 1H), 6.12 (s, 1H), 5.86 (s, 1H),3.99 (s, 3H), 3.40 (s, 3H), 2.26-2.37 (m, 3H), 2.13-2.20 (m, 1H),1.92-2.04 (m, 4H), 1.82-1.90 (m, 3H), 1.69 (d, J=6.8 Hz, 4H), 1.38-1.64(m, 10H), 1.36 (s, 9H), 1.30 (d, J=6.9 Hz, 6H), 1.22 (d, J=6.8 Hz, 3H),0.98 (d, J=6.8 Hz, 3H), 0.82 (t, J=6.9 Hz, 6H) ppm. ³¹P{¹H}(Methanol-d₄, 121 MHz): 65.78 ppm.

Synthetic Procedures for Large Scale Syntheses of 3d and 4d:

PdCl₂ (13.9 g, 78.5 mmol) and NaCl (9.19 g, 157.0 mmol) were added to a1 L round bottom flask. MeOH (600 mL) was added and the reaction mixtureheated at 50° C. for 90 minutes, at which time it became homogeneous.The solution was allowed to cool to room temperature. 1-^(t)Bu-Indene(13.5 g, 78.5 mmol) was added followed by NaHCO₃ (9.88 g, 117.75 mmol)and the reaction stirred for 6 hours at room temperature. The reactionmixture was filtered and the resulting black solid washed with MeOH,water and diethyl ether. The solid was dissolved in dichloromethane andthe solution passed through a pad of celite. The solvent was removedusing a rotary evaporator to yield a brown solid. The product was driedunder vacuum to yield 3d as a brown solid. Yield: 21.6 g, 88%.

(η³-1-^(t)Bu-indenyl)₂(μ-Cl)₂Pd₂ (1d) (6.00 g, 9.58 mmol) and IPr (7.44g, 19.16 mmol) were added to a 500 mL Schlenk flask. Diethyl ether (200mL) was added to the flask via cannula. The resulting solution wasstirred for 120 minutes. The solution was passed through a pad of silicagel, followed by the removal of solvent using a rotary evaporator togive 4d-IPr as an orange powder. Yield: 12.1 g, 91%.

Example 2 Synthesis of [(1-^(t)Bu-Indenyl)Pd(DPPF)]Cl

In a nitrogen filled glove box, [(1-^(t)Bu-Indenyl)Pd(μ-Cl)]₂ (100 mg,0.16 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (DPPF) (177 mg, 0.32mmol) were added to a 100 mL Schlenk flask. Methanol (20 mL) was addedand the mixture was stirred at room temperature for 2 hours. During thistime, the mixture became homogenous with a deep red color. The flask wasopened to air and the solvent was removed with a rotary evaporator toyield a red oil.

Pentane was added, followed by sonication; vacuum filtration produced ared crystalline solid (225 mg, 81%).

Example 3 Synthesis of [(1-^(t)Bu-Indenyl)Pd(NiXantPhos)]₄

In a nitrogen filled glove box, [(1-^(t)Bu-Indenyl)Pd(μ-Cl)]₂ (57 mg,0.091 mmol) and silver tetrafluoroborate (42 mg, 0.218 mmol) were addedto a 100 mL Schlenk flask. Methanol (10 mL) was added to the flask andthe mixture was stirred for one hour. In a second 100 mL Schlenk flask,NiXantPhos (100 mg, 0.182 mmol) was added with methanol (10 mL). Thecontents of the first Schlenk flask were transferred to the second usinga filter cannula, removing the silver chloride byproduct. The secondSchlenk flask was stirred for an additional hour at room temperature,during which time the mixture became homogeneous. The solvent wasremoved under reduced pressure, followed by addition of pentane. After10 minutes of sonication, vacuum filtration yielded the compound as anorange powder (143 mg, 86%).

Example 4 Yields of Product for the Suzuki-Miyaura Reaction Catalyzed byComplexes 2-IPr, PEPPSI-IPr, 4a-IPr, 4b-IPr, 4c-IPr and 4d-IPr (FIG. 3).

The experiments employing KO^(t)Bu as a base in FIG. 3 used a MeOHsolution containing 0.5263 M 4-chlorotoluene, 0.5525 M phenylboronicacid, 0.5789 M K^(t)OBu and 0.2632 M naphthalene. The experimentsemploying K₂CO₃ as base in FIG. 3 used a MeOH solution containing 0.5263M 4-chlorotoluene, 0.5525 M phenylboronic acid and 0.2632 M naphthalene.Details of how the stock solutions were prepared are given below.

KO^(t)Bu Experiments:

KO^(t)Bu (0.650 g, 5.79 mmol), phenylboronic acid (0.674 g, 5.531 mmol)and naphthalene (0.3373 g, 2.632 mmol) were transferred to a 10 mLvolumetric flask in a glove box. The volumetric flask was capped with arubber septum and placed under dinitrogen on a Schlenk line.4-chlorotoluene (0.6232 mL, 5.268 mmol) was transferred to thevolumetric flask using a 1.0 mL glass syringe. The contents weredissolved in MeOH, and the solution was diluted to 10 mL. The solutionwas then transferred to a flask with a Kontes valve.

K₂CO₃ Experiments:

Phenylboronic acid (0.674 g, 5.531 mmol) and naphthalene (0.3373 g,2.632 mmol) were transferred to a 10 mL volumetric flask in a glove box.The volumetric flask was capped with a rubber septum and placed underdinitrogen on a Schlenk line. 4-chlorotoluene (0.6232 mL, 5.268 mmol)was transferred to the volumetric flask using a 1.0 mL glass syringe.The contents were dissolved in MeOH, and the solution was diluted to 10mL. The solution was then transferred to a flask with a Kontes valve.

The concentration of the precatalyst stock solutions differed dependingon the base being used in the experiment.

THF Stock Solutions for 2-IPr, PEPPSI-IPr and 4a-IPr-4d-IPr for KO^(t)BuExperiments:

0.05 mmol of the precatalyst was transferred into a 1 mL volumetricflask on the bench top. The flask was capped with a septum, and placedunder dinitrogen (by cycling three times between vacuum and dinitrogen)on a Schlenk line. The precatalyst was dissolved in THF, and thesolution was diluted to 1 mL. The solution was transferred to a flaskwith a Kontes valve.

THF Stock Solutions for 2-IPr, PEPPSI-IPr and 4a-IPr-4d-IPr for K₂CO₃Experiments:

The precatalyst (0.1 mmol) was transferred into a 1 mL volumetric flaskon the bench top. The flask was capped with a septum, and placed underdinitrogen (by cycling three times between vacuum and dinitrogen) on aSchlenk line. The precatalyst was dissolved in THF, and the solution wasdiluted to 1 mL. The solution was transferred to a flask with a Kontesvalve.

Example 5 Experimental Details for Heterogeneous Catalytic ExperimentsUsing ^(t)PrOH as Solvent and KO^(t)Bu as Base (Nolan's OriginalConditions)

Phenylboronic acid (64.0 mg, 0.525 mmol), 4-chlorotoluene (59 μL, 0.50mmol), KO^(t)Bu (61.7 mg, 0.55 mmol) and naphthalene (32.1 mg, 0.25mmol) were added to a 1 dram vial equipped with a flea stir bar. Underan atmosphere of dinitrogen, 1 mL of degassed ^(i)PrOH was added viasyringe to the mixture and sealed with a septum cap. The vial was thenheated using an aluminum block heater set to 25° C. After thermalequilibration, the reaction was initiated via the addition of 50 μL ofthe appropriate precatalyst solution in ^(i)PrOH (0.05 M [Pd]). Aliquots(˜50-100 μL) were removed at reaction times indicated. The aliquots werepurified by filtration through pipet filters containing approximately 1cm of silica and eluted with 1-1.2 mL of ethyl acetate directly into GCvials. Conversion was determined by comparison of the GC responses ofproduct and the internal naphthalene standard. A comparison of theperformation of 2-IPr and 2d-IPr under these conditions is given inTable 6.

TABLE 6 Yields^(a) of product for the Suzuki-Miyaura reaction performedusing ^(i)PrOH as solvent and KO^(t)Bu as base.

Time % Yields for Precatalysts (min) 2-IPr 4d-IPr 15 4 15 30 10 35 45 1854 60 29 78 120 47 >99 ^(a)Yields were calculated using gaschromatography with naphthalene as an internal standard and are theaverage of two runs.

Example 6 Experiments Involving Pd(I) Dimers

Experimental Details for Equation 2; Reaction of 4d-IPr with K₂CO₃ ind₄-MeOH

4d-IPr (10.0 mg, 0.0144 mmol) was dissolved in 500 μL of d₄-MeOH. K₂CO₃(4.0 mg, 0.0288 mmol) was added to a J. Young NMR tube. The solution wastransferred to the tube at −78° C. and subsequently degassed on aSchlenk line and put under an atmosphere of dinitrogen. Theheterogeneous reaction was sonicated for two hours, at which time thesolvent was removed under reduced pressure on a Schlenk line. d₆-benzenewas added to solubilize the products (although Pd black remainedinsoluble) and a ¹H NMR spectrum was recorded. The only Pd containingpeaks present corresponded to Pd(IPr)₂.

Catalysis Using 4a-IPr Under NMR Conditions:

In a glovebox, phenylboronic acid (10.0 mg, 0.082 mmol), 4-chlorotoluene(9.2 μL, 0.0781 mmol), KO^(t)Bu (9.6 mg, 0.0859 mmol) and2,6-dimethoxytoluene (6.0 mg, 0.039 mmol) were dissolved in 400 μL ofd₄-MeOH. 4a-IPr (2.5 mg, 0.0031 mmol) was dissolved in 100 μL of d₈-THF.These solutions were combined in a J. Young NMR tube and the reactionwas monitored by ¹H NMR spectroscopy for one hour at 25° C. After thistime, the solvent mixture was removed on a Schlenk line and d₆-benzenewas added. A final ¹H NMR spectrum was recorded to identify the Pdcontaining products of the reaction. 7-IPr was observed as the main Pdcontaining product, with a yield of 85% compared to the internalstandard 2,6-dimethoxytoluene.

Example 7 Substrate Scope Using IPr as Ancillary Ligand

Experimental Details for Table 4: Yields of Product for a Series ofSuzuki-Miyaura Reactions Catalyzed by 4d-IPr and 2-IPr

All catalytic reactions were performed under the same concentration andthe stock solutions were prepared in the following representativemanner:

KO^(t)Bu Experiments:

KO^(t)Bu (0.650 g, 5.79 mmol), boronic acid (5.531 mmol) and naphthalene(0.3373 g, 2.632 mmol) were transferred to a 10 mL volumetric flask in aglove box. The volumetric flask was capped with a rubber septum andplaced under dinitrogen on a Schlenk line. Aryl chloride (5.268 mmol)was transferred to the volumetric flask using a 1.0 mL glass syringe.The contents were dissolved in MeOH, and the solution was diluted to 10mL. The solution was then transferred to a flask with a Kontes valve.

K₂CO₃ Experiments:

Boronic acid (5.531 mmol) and naphthalene (0.3373 g, 2.632 mmol) weretransferred to a 10 mL volumetric flask in a glove box. The volumetricflask was capped with a rubber septum and placed under dinitrogen on aSchlenk line. Aryl chloride (5.268 mmol) was transferred to thevolumetric flask using a 1.0 mL glass syringe. The contents weredissolved in MeOH, and the solution was diluted to 10 mL. The solutionwas then transferred to a flask with a Kontes valve.

Precatalyst Stock Solutions Used in 0.1 mol % Reactions:

0.01 mmol of 2-IPr or 4d-IPr was transferred into a 1 mL volumetricflask on the bench top. The flask was capped with a septum, and placedunder dinitrogen (by cycling three times between vacuum and dinitrogen)on a Schlenk line. The precatalyst was dissolved in THF, and thesolution was diluted to 1 mL. The solution was transferred to a flaskwith a Kontes valve.

Precatalyst Stock Solutions Used in 0.2 mol % Reactions:

0.02 mmol of 2-IPr or 4d-IPr was transferred into a 1 mL volumetricflask on the bench top. The flask was capped with a septum, and placedunder dinitrogen (by cycling three times between vacuum and dinitrogen)on a Schlenk line. The precatalyst was dissolved in THF, and thesolution was diluted to 1 mL. The solution was transferred to a flaskwith a Kontes valve.

Precatalyst Stock Solutions Used in 0.5 mol % Reactions: 0.05 mmol of2-IPr or 4d-IPr was transferred into a 1 mL volumetric flask on thebench top. The flask was capped with a septum, and placed underdinitrogen (by cycling three times between vacuum and dinitrogen) on aSchlenk line. The precatalyst was dissolved in THF, and the solution wasdiluted to 1 mL. The solution was transferred to a flask with a Kontesvalve.

Precatalyst Stock Solutions Used in 1.0 mol % REACTIONS:

2-IPr or 4d-IPr (0.1 mmol) was transferred into a 1 mL volumetric flaskon the bench top. The flask was capped with a septum, and placed underdinitrogen (by cycling three times between vacuum and dinitrogen) on aSchlenk line. The precatalyst was dissolved in THF, and the solution wasdiluted to 1 mL. The solution was transferred to a flask with a Kontesvalve.

Example 8 Tetra-Ortho Substituted Suzuki Miyaura Reactions UsingIPr*^(OMe) General Procedure A:

In a nitrogen filled glove box, aryl halide (0.5 mmol), if solid,boronic acid (0.75 mmol), KOH (1.0 mmol) and 4d-IPr*^(OMe) (0.005 mmol,0.5 mol % or 0.01 mmol, 1.0 mol %) were added to a 1 dram vial equippedwith a magnetic stir bar. Aryl chloride (0.5 mmol), if liquid, was addedby syringe, followed by THF (1 mL). The vial was sealed and stirredoutside of the glove box at 80° C. for 12 hours. At this point, the vialwas opened to air and diethyl ether (10 mL) and H₂O (10 mL) were addedto the reaction mixture. The aqueous phase was extracted with diethylether (3×10 mL). The combined organic phases were dried over MgSO₄ andfiltered. The supernatant was then passed through a pad of silica gel,followed by removal of the solvent under reduced pressure to give theorganic product.

¹H NMR data for the following compounds were consistent with thosepublished in Bastug & Nolan, 2014, Organometallics 33:1253-1258.

2-Methoxy-1-(2,3,5,6-tetramethylphenyl)naphthalene. Following GeneralProcedure A, a mixture of 1-bromo-2-methoxynaphthalene (118 mg, 0.5mmol), 2,3,5,6-tetramethylphenyl boronic acid (133 mg, 0.75 mmol),potassium hydroxide (56 mg, 1.0 mmol), 4d-IPr*^(OMe) (3.2 mg, 0.0025mmol) and THF (1 mL) was stirred at 80° C. for 12 hours. The average oftwo runs provided a yield of 94% (136 mg).

4-Mesityl-1,3,5-trimethyl-1H-pyrazole. Following General Procedure A, amixture of 4-bromo-1,3,5-trimethyl-1H-pyrazole (92 mg, 0.5 mmol),2,4,6-trimethylphenyl boronic acid (123 mg, 0.75 mmol), potassiumhydroxide (56 mg, 1.0 mmol), 4d-IPr*^(OMe) (3.2 mg, 0.0025 mmol) and THF(1 mL) was stirred at 80° C. for 12 hours. The average of two runsprovided a yield of 95% (108 mg).

1-Mesityl-2-methylnaphthalene. Following General Procedure A, a mixtureof 1-bromo-2-methylnaphthalene (78 μL, 0.5 mmol), 2,4,6-trimethylphenylboronic acid (123 mg, 0.75 mmol), potassium hydroxide (56 mg, 1.0 mmol),4d-IPr*^(OMe) (3.2 mg, 0.0025 mmol) and THF (1 mL) was stirred at 80° C.for 12 hours. The average of two runs provided a yield of 98% (127 mg).

2,6-dimethyl-2′,6′-dimethoxy-1,1′-biphenyl. Following General ProcedureA, a mixture of 2-chloro-m-xylene (66 μL, 0.5 mmol), 2,6-dimethoxyphenylboronic acid (137 mg, 0.75 mmol), potassium hydroxide (56 mg, 1.0 mmol),4d-IPr*^(OMe) (3.2 mg, 0.0025 mmol) and THF (1 mL) was stirred at 80° C.for 12 hours. The average of two runs provided a yield of 94% (114 mg).

2,2′,4,6,6′-pentamethyl-1,1′-biphenyl. Following General Procedure A, amixture of 2-chloro-m-xylene (66 μL, 0.5 mmol), 2,4,6-trimethylphenylboronic acid (123 mg, 0.75 mmol), potassium hydroxide (56 mg, 1.0 mmol),4d-IPr*^(OMe) (3.2 mg, 0.0025 mmol) and THF (1 mL) was stirred at 80° C.for 12 hours. The average of two runs provided a yield of 82% (92 mg).

2,2′,3,5,6,6′-hexamethyl-1,1′-biphenyl. Following General Procedure A, amixture of 2-chloro-m-xylene (66 μL, 0.5 mmol),2,3,5,6-tetramethylphenyl boronic acid (133 mg, 0.75 mmol), potassiumhydroxide (56 mg, 1.0 mmol), 4d-IPr*^(OMe) (3.2 mg, 0.0025 mmol) and THF(1 mL) was stirred at 80° C. for 12 hours. The average of two runsprovided a yield of 92% (110 mg).

Example 9 Suzuki-Miyaura Reactions With Heterocyclic Boronic Acid UsingXPhos General Procedure B:

In a nitrogen filled glove box, aryl chloride (1.0 mmol), if solid,boronic acid (1.5 mmol), K₂CO₃ (2.0 mmol) and 4d-XPhos (0.01 mmol, 1 mol%) were added to a 4 dram vial equipped with a magnetic stir bar. Arylchloride (1.0 mmol), if liquid, was added by syringe, followed bymethanol (4 mL) and THF (2 mL). The vial was sealed and stirred outsideof the glove box at room temperature or 40° C. for one hour. At thispoint, the vial was opened to air and diethyl ether (10 mL) and H₂O (10mL) were added to the reaction mixture. The aqueous phase was extractedwith diethyl ether (3×10 mL). The combined organic phases were driedover MgSO₄ and filtered. The supernatant was then passed through a padof silica gel, followed by removal of the solvent under reduced pressureto give the organic product.

¹H NMR data (and ¹⁹F NMR data, if applicable) for the followingcompounds were consistent with those published in Kinzel, et al., 2010,J. Am. Chem. Soc. 2010, 132, 14073-14075; and/or Bruno, et al., 2013,Chem. Sci. 4:916-920.

2-(3-(trifluoromethyl)benzyl)furan. Following General Procedure B, amixture of 1-(chloromethyl)-3-(trifluoromethyl)benzene (151 μL, 1.0mmol), 2-furan boronic acid (168 mg, 1.5 mmol), K₂CO₃ (276 mg, 2.0mmol), 4d-XPhos (7.9 mg, 0.01 mmol), THF (2 mL), and methanol (4 mL)were stirred at 40° C. for one hour. The average of two runs provided ayield of 92% (210 mg).

4-(furan-2-yl)-2-isopropyl-5-methylphenol. Following General ProcedureB, a mixture of 4-chloro-2-isopropyl-5-methylphenol (185 μg, 1.0 mmol),2-furan boronic acid (168 mg, 1.5 mmol), K₂CO₃ (276 mg, 2.0 mmol),4d-XPhos (7.9 mg, 0.01 mmol), THF (2 mL), and methanol (4 mL) werestirred at RT for one hour. The average of two runs provided a yield of94% (203 mg).

2-(benzofuran-2-yl)-4,6-dimethoxypyrimidine. Following General ProcedureB, a mixture of 2-chloro-4,6-dimethoxypyrimidine (175 μg, 1.0 mmol),benzofuran-2-boronic acid (243 mg, 1.5 mmol), K₂CO₃ (276 mg, 2.0 mmol),4d-XPhos (7.9 mg, 0.01 mmol), THF (2 mL), and methanol (4 mL) werestirred at 40° C. for one hour. The average of two runs provided a yieldof 95% (244 mg).

5-(benzofuran-2-yl)-1H-indole. Following General Procedure B, a mixtureof 4-chloroindole (152 μg, 1.0 mmol), benzofuran-2-boronic acid (243 mg,1.5 mmol), K₂CO₃ (276 mg, 2.0 mmol), 4d-XPhos (7.9 mg, 0.01 mmol), THF(2 mL), and methanol (4 mL) were stirred at 40° C. for one hour. Theaverage of two runs provided a yield of 94% (220 mg).

2-(perfluorophenyl)thiophene. Following General Procedure B, a mixtureof pentafluorochlorobenzene (130 μL, 1.0 mmol), 2-thiophene boronic acid(192 mg, 1.5 mmol), K₂CO₃ (276 mg, 2.0 mmol), 4d-XPhos (7.9 mg, 0.01mmol), THF (2 mL), and methanol (4 mL) were stirred at RT for one hour.The average of two runs provided a yield of 93% (232 mg).

2-(benzo[b]thiophen-2-yl)quinoline. Following General Procedure B, amixture of 2-chloroquinoline (164 μg, 1.0 mmol),benzothiophene-2-boronic acid (267 mg, 1.5 mmol), K₂CO₃ (276 mg, 2.0mmol), 4d-XPhos (7.9 mg, 0.01 mmol), THF (2 mL), and methanol (4 mL)were stirred at 40° C. for one hour. Dichloromethane was used for workup, instead of diethyl ether, due to factors associated with solubility.The average of two runs provided a yield of 98% (220 mg).

3-(thiophen-2-yl)furan. Following General Procedure B, a mixture of2-chlorothiophene (92 μL, 1.0 mmol), 3-furan boronic acid (168 mg, 1.5mmol), K₂CO₃ (276 mg, 2.0 mmol), 4d-XPhos (7.9 mg, 0.01 mmol), THF (2mL), and methanol (4 mL) were stirred at 40° C. for one hour. Theaverage of two runs provided a yield of 95% (143 mg).

tert-butyl 4-(4-(thiophen-3-yl)phenyl)piperazine-1-carboxylate.Following General Procedure B, a mixture oftent-butyl-(4-chlorophenyl)-carbamate (228 mg, 1.0 mmol), 3-thiopheneboronic acid (192 mg, 1.5 mmol), K₂CO₃ (276 mg, 2.0 mmol), 4d-XPhos (7.9mg, 0.01 mmol), THF (2 mL), and methanol (4 mL) were stirred at RT forone hour. The average of two runs provided a yield of 95% (143 mg).

Example 10 Suzuki-Miyaura Reactions With Indazoles or BenzimidazolesUsing SPhos General Procedure C:

In a nitrogen filled glove box, aryl chloride (1.0 mmol), boronic acid(2.0 mmol), K₂CO₃ (2.0 mmol) and 4d-SPhos (0.02 mmol, 2 mol %) wereadded to a 4 dram vial equipped with a magnetic stir bar. Methanol (4mL) and 1,4-dioxane (2 mL) were added via syringe. The vial was sealedand stirred outside of the glove box in a pre-calibrated oil bath at 80°C. for 15 hours. At this time, the vial was opened to air and ethylacetate (10 mL) and H₂O (10 mL) were added. The aqueous phase wasextracted with ethyl acetate (3×10 mL) and the combined organic phasewas dried over MgSO₄. After filtration, the supernatant was passedthrough a pad of silica gel and celite and washed with ethyl acetate.The solvent was removed under reduced pressure to give the organicproduct.

¹H NMR data for the following compounds were consistent with thosepublished in Düffert, et al., 2013, J. Am. Chem. Soc. 135:12877-12885.

3-(thiophen-3-yl)-1H-indazole. Following General Procedure C, a mixtureof 3-chloro indazole (153 mg, 1.0 mmol), 3-thiophene boronic acid (256mg, 2.0 mmol), K₂CO₃ (276 mg, 2.0 mmol), 4d-SPhos (14.5 mg, 0.02 mmol),1,4-dioxane (4 mL) and methanol (2 mL) were stirred at 80° C. for 15hours. The average of two runs provided a yield of 98% (196 mg).

3-(furan-3-yl)-1H-indazole. Following General Procedure C, a mixture of3-chloro indazole (153 mg, 1.0 mmol), 3-furan boronic acid (224 mg, 2.0mmol), K₂CO₃ (276 mg, 2.0 mmol), 4d-SPhos (14.5 mg, 0.02 mmol),1,4-dioxane (4 mL) and methanol (2 mL) were stirred at 80° C. for 15hours. The average of two runs provided a yield of 97% (177 mg).

4-(1H-indazol-3-yl)benzonitrile. Following General Procedure C, amixture of 3-chloro indazole (153 mg, 1.0 mmol), 4-cyanophenyl boronicacid (294 mg, 2.0 mmol), K₂CO₃ (276 mg, 2.0 mmol), 4d-SPhos (14.5 mg,0.02 mmol), 1,4-dioxane (4 mL) and methanol (2 mL) were stirred at 80°C. for 15 hours. The average of two runs provided a yield of 90% (197mg).

2-(thiophen-3-yl)-1H-benzo[d]imidazole. Following General Procedure C, amixture of 2-chlorobenzimidazole (153 mg, 1.0 mmol), 3-thiophene boronicacid (256 mg, 2.0 mmol), K₂CO₃ (276 mg, 2.0 mmol), 4d-SPhos (14.5 mg,0.02 mmol), 1,4-dioxane (4 mL) and methanol (2 mL) were stirred at 80°C. for 15 hours. The average of two runs provided a yield of 98% (198mg).

2-(4-tert-butylphenyl)-1H-benzo[d]imidazole. Following General ProcedureC, a mixture of 2-chlorobenzimidazole (153 mg, 1.0 mmol),4-tert-butylphenyl boronic acid (356 mg, 2.0 mmol), K₂CO₃ (276 mg, 2.0mmol), 4d-SPhos (14.5 mg, 0.02 mmol), 1,4-dioxane (4 mL) and methanol (2mL) were stirred at 80° C. for 15 hours. The average of two runsprovided a yield of 94% (236 mg).

1-(3-(1H-benzo[d]imidazol-2-yl)phenyl)ethanone. Following GeneralProcedure C, a mixture of 2-chlorobenzimidazole (153 mg, 1.0 mmol),3-acetylphenyl boronic acid (328 mg, 2.0 mmol), K₂CO₃ (276 mg, 2.0mmol), 4d-SPhos (14.5 mg, 0.02 mmol), 1,4-dioxane (4 mL) and methanol (2mL) were stirred at 80° C. for 15 hours. The average of two runsprovided a yield of 91% (214 mg).

Example 11 Buchwald-Hartwig Reactions Using RuPhos General Procedure D:

In a nitrogen filled glove box, aryl halide (1.0 mmol), if solid, amine(1.2 mmol), if solid, NaO^(t)Bu (115 mg, 1.2 mmol), 4d-RuPhos (4.0 mg,0.005 mmol) and RuPhos (2.3 mg, 0.005 mmol) were added to a 1 dram vialequipped with a magnetic stir bar. Amine (1.2 mmol), if liquid, and arylhalide (1.0 mmol), if liquid, were added via syringe along with THF (1mL). The vial was sealed and stirred outside the glove box in apre-calibrated heating block for 6 hours at 85° C. At this time, thevial was cooled to room temperature and ethyl acetate (10 mL) and water(10 mL) were added. The aqueous phase was extracted with ethyl acetate(3×10 mL); the organic phase was dried over MgSO₄ and subsequentlyfiltered. The supernatant was passed through a pad of silica gel,followed by evaporation of the solvent to give the organic product.

¹H NMR data for the following compounds were consistent with thosepublished in Bruno, et al., 2013, Chem. Sci. 4:916-920.

5-methyl-N,N-diphenylpyridin-2-amine. Following General Procedure D, amixture of 2-chloro-5-methylpyridine (110 μL, 1.0 mmol), diphenylamine(203 mg, 1.2 mmol), NaO^(t)Bu (115 mg, 1.2 mmol), 4d-RuPhos (4.0 mg,0.005 mmol), RuPhos (2.3 mg, 0.005 mmol) and THF (1 mL) were stirred at85° C. for 6 hours. The average of two runs provided a yield of 94% (244mg).

N-methyl-N-phenethylpyridin-3-amine. Following General Procedure D, amixture of 3-chloropyridine (96 μL, 1.0 mmol), N-methylphenethyl amine(174 μL, 1.2 mmol), NaO^(t)Bu (115 mg, 1.2 mmol), 4d-RuPhos (4.0 mg,0.005 mmol), RuPhos (2.3 mg, 0.005 mmol) and THF (1 mL) were stirred at85° C. for 6 hours. The average of two runs provided a yield of 96% (204mg).

4-(2-methoxyphenyl)morpholine. Following General Procedure D, a mixtureof 2-chloroanisole (122 μL, 1.0 mmol), morpholine (104 μL, 1.2 mmol),NaO^(t)Bu (115 mg, 1.2 mmol), 4d-RuPhos (4.0 mg, 0.005 mmol), RuPhos(2.3 mg, 0.005 mmol) and THF (1 mL) were stirred at 85° C. for 6 hours.The average of two runs provided a yield of 96% (185 mg).

N-methyl-N-(pyridin-4-yl)quinolin-6-amine. Following General ProcedureD, a mixture of 6-chloroquinoline (164 mg, 1.0 mmol),N-methyl-4-aminopyridine (130 mg, 1.2 mmol), NaO^(t)Bu (115 mg, 1.2mmol), 4d-RuPhos (4.0 mg, 0.005 mmol), RuPhos (2.3 mg, 0.005 mmol) andTHF (1 mL) were stirred at 85° C. for 6 hours. The average of two runsprovided a yield of 91% (214 mg).

N,N-dibutyl-4-methoxy-3-methylaniline. Following General Procedure D, amixture of 4-bromo-2-methylanisole (201 mg, 1.0 mmol), di-n-butylamine(202 μL, 1.2 mmol), NaO^(t)Bu (115 mg, 1.2 mmol), 4d-RuPhos (4.0 mg,0.005 mmol), RuPhos (2.3 mg, 0.005 mmol) and THF (1 mL) were stirred at85° C. for 6 hours. The average of two runs provided a yield of 90% (224mg).

N-benzyl-2-methyl-N-phenylquinolin-7-amine. Following General ProcedureD, a mixture of 7-chloro-2-methylquinoline (177 mg, 1.0 mmol),N-benzylaniline (220 mg, 1.2 mmol), NaO^(t)Bu (115 mg, 1.2 mmol),4d-RuPhos (4.0 mg, 0.005 mmol), RuPhos (2.3 mg, 0.005 mmol) and THF (1mL) were stirred at 85° C. for 6 hours. The average of two runs provideda yield of 82% (265 mg).

Example 12 Alpha-Arylation Reactions Using XPhos General Procedure E:

In a nitrogen filled glove box, KO^(t)Bu (112 mg, 1.0 mmol) and 4d-XPhos(4.0 mg, 0.005 mmol) were added to a one dram vial equipped with amagnetic stir bar. Aryl chloride (0.525 mmol) and aryl methyl ketone(0.5 mmol) were added to the vial via syringe. THF (1 mL) and methanol(1 mL) were added, and the vial was sealed and stirred outside of theglove box in a pre-calibrated heating block for one hour at 60° C. Atthis time, an aqueous solution of NH₄Cl (10 mL) was added. The productwas extracted with ethyl acetate (3×10 mL), which was then dried overMgSO₄ and filtered. The resulting supernatant was passed through a padof silica gel, followed by removal of the solvent under reduced pressureto give the organic product.

¹H NMR for the following compounds were consistent with those publishedin Biscoe & Buchwald, 2009, Org. Lett. 11:1773-1775.

2-(4-Methoxyphenyl)-1-phenylethanone. Following General Procedure E, amixture of acetophenone (59 μL, 0.5 mmol), 4-chloroanisole (64 μL, 0.525mmol), KO^(t)Bu (112 mg, 1.0 mmol), 4d-XPhos (4.0 mg, 0.005 mmol), THF(1 mL) and methanol (1 mL) were stirred at 60° C. for 1 hour. Theaverage of two runs provided a yield of 97% (110 mg).

2-(4-Methoxyphenyl)-1-(thiophen-2-yl)ethanone. Following GeneralProcedure E, a mixture of 2-acetylthiophene (54 μL, 0.5 mmol),4-chloroanisole (64 μL, 0.525 mmol), KO^(t)Bu (112 mg, 1.0 mmol),4d-XPhos (4.0 mg, 0.005 mmol), THF (1 mL) and methanol (1 mL) werestirred at 60° C. for 1 hour. The average of two runs provided a yieldof 90% (105 mg).

2-(4-Methoxyphenyl)-1-(pyridin-3-yl)ethanone. Following GeneralProcedure E, a mixture of 3-acetylpyridine (55 μL, 0.5 mmol),4-chloroanisole (64 μL, 0.525 mmol), KO^(t)Bu (112 mg, 1.0 mmol),4d-XPhos (4.0 mg, 0.005 mmol), THF (1 mL) and methanol (1 mL) werestirred at 60° C. for 1 hour. The average of two runs provided a yieldof 93% (106 mg).

1-(2,5-Dimethylthiophen-3-yl)-2-(4-methoxyphenyl)ethanone. FollowingGeneral Procedure E, a mixture of 1-(2,5-dimethyl-3-thienyl)-ethanone(72 μL, 0.5 mmol), 4-chloroanisole (64 μL, 0.525 mmol), KO^(t)Bu (112mg, 1.0 mmol), 4d-XPhos (4.0 mg, 0.005 mmol), THF (1 mL) and methanol (1mL) were stirred at 60° C. for 1 hour. The average of two runs provideda yield of 95% (124 mg).

1-Phenyl-2-(pyridin-3-yl)ethanone. Following General Procedure E, amixture of acetophenone (59 μL, 0.5 mmol), 3-chloropyridine (50 μL,0.525 mmol), KO^(t)Bu (112 mg, 1.0 mmol), 4d-XPhos (4.0 mg, 0.005 mmol),THF (1 mL) and methanol (1 mL) were stirred at 60° C. for 1 hour. Theaverage of two runs provided a yield of 94% (92 mg).

1,2-Di(pyridin-3-yl)ethanone. Following General Procedure E, a mixtureof 3-acetylpyridine (55 μL, 0.5 mmol), 3-chloropyridine (50 μL, 0.525mmol), KO^(t)Bu (112 mg, 1.0 mmol), 4d-XPhos (4.0 mg, 0.005 mmol), THF(1 mL) and methanol (1 mL) were stirred at 60° C. for 1 hour. Theaverage of two runs provided a yield of 91% (90 mg).

1-(2,5-Dimethylthiophen-3-yl)-2-(pyridin-3-yl)ethanone. FollowingGeneral Procedure E, a mixture of 1-(2,5-dimethyl-3-thienyl)-ethanone(72 μL, 0.5 mmol), 3-chloropyridine (50 μL, 0.525 mmol), KO^(t)Bu (112mg, 1.0 mmol), 4d-XPhos (4.0 mg, 0.005 mmol), THF (1 mL) and methanol (1mL) were stirred at 60° C. for 1 hour. The average of two runs provideda yield of 92% (106 mg).

Example 13 Suzuki-Miyaura Reactions with Alkyl Trifluoroboronates usingP^(t)Bu₃ General Procedure F:

In a nitrogen filled glove box, potassium alkyl trifluoroboronate salt(0.75 mmol), K₂CO₃ (207 mg, 1.5 mmol), 4d-P^(t)Bu₃ (2.6 mg or 5.2 mg,0.005 mmol or 0.01 mmol) and aryl chloride (0.5 mmol), if solid, wereadded to a one dram vial equipped with a magnetic stir bar. Arylchloride (0.5 mmol), if liquid, was added via syringe, followed byaddition of toluene (1 mL) and water (0.5 mL). The reaction was stirredoutside of the glove box in a pre-calibrated heating block at 80° C. for8 hours. At this time, aqueous NH₄Cl (10 mL) was added. Ethyl acetate(3×10 mL) was used to extract the product, which was then subsequentlydried over MgSO₄ and filtered. The supernatant was passed through a padof silica gel, followed by evaporation of the solvent via reducedpressure to give the organic product.

¹H NMR for the following compounds were consistent with those publishedin Li, et al., 2014, J. Am. Chem. Soc. 136:14027-14030.

4-iso-propylanisole. Following General Procedure F, a mixture of4-chloroanisole (61 μL, 0.5 mmol), potassium iso-propyltrifluoroborate(113 mg, 0.75), K₂CO₃ (207 mg, 1.5 mmol), 4d-P^(t)Bu₃ (5.2 mg, 0.01mmol), toluene (1 mL) and H₂O (0.5 mL) were stirred at 80° C. for 8hours. The average of two runs provided a yield of 95% (72 mg).

3-(sec-Butyl)-anisole. Following General Procedure F, a mixture of3-chloroanisole (61 μL, 0.5 mmol), potassium sec-butyltrifluoroborate(123 mg, 0.75), K₂CO₃ (207 mg, 1.5 mmol), 4d-P^(t)Bu₃ (2.6 mg, 0.005mmol), toluene (1 mL) and H₂O (0.5 mL) were stirred at 80° C. for 8hours. The average of two runs provided a yield of 94% (77 mg).

1-Cyclopropyl-4-nitrobenzene. Following General Procedure F, a mixtureof 4-chloro nitrobenzene (79 mg, 0.5 mmol), potassiumcyclopropyltrifluoroborate (123 mg, 0.75), K₂CO₃ (207 mg, 1.5 mmol),4d-P^(t)Bu₃ (2.6 mg, 0.005 mmol), toluene (1 mL) and H₂O (0.5 mL) werestirred at 40° C. for 8 hours. The average of two runs provided a yieldof 97% (79 mg).

6-Cyclopentylquinoline. Following General Procedure F, a mixture of6-chloroquinoline (82 mg, 0.5 mmol), potassiumcyclopentyltrifluoroborate (132 mg, 0.75), K₂CO₃ (207 mg, 1.5 mmol),4d-P^(t)Bu₃ (5.6 mg, 0.01 mmol), toluene (1 mL) and H₂O (0.5 mL) werestirred at 80° C. for 8 hours. The average of two runs provided a yieldof 89% (88 mg).

3-cyclohexylanisole. Following General Procedure F, a mixture of3-chloroanisole (61 μL, 0.5 mmol), potassium cyclohexyltrifluoroborate(143 mg, 0.75), K₂CO₃ (207 mg, 1.5 mmol), 4d-P^(t)Bu₃ (5.6 mg, 0.01mmol), toluene (1 mL) and H₂O (0.5 mL) were stirred at 80° C. for 8hours. The average of two runs provided a yield of 86% (83 mg).

Example 14: Assorted catalytic reactions using in situ generatedprecatalysts

In a nitrogen filled glove box, 3d (15.5 mg, 0.025 mmol) and XPhos (24mg, 0.05 mmol) were added to a 2 dram vial equipped with a magnetic stirbar. THF (5 mL) was added to the vial via syringe; the mixture wasstirred for 10 minutes. In a 4 dram vial,2-chloro-4,6-dimethoxyprimidine (175 mg, 1.0 mmol), benzofuran-2-boronicacid (243 mg, 1.5 mmol) and K₂CO₃ (276 mg, 2.0 mmol) were added with amagnetic stir bar. THF (1 mL) and methanol (4 mL) were added to the vialvia syringe, followed by 1 mL of the THF/precatalyst solution. The vialwas sealed and stirred outside of the glove box in a pre-calibratedheating block at 40° C. for one hour. General Procedure B was followedto yield the product in a 95% yield (242 mg).

In a nitrogen filled glove box, 3d (31.0 mg, 0.05 mmol) and SPhos (41mg, 0.1 mmol) were added to a 2 dram vial equipped with a magnetic stirbar. 1,4-dioxane (5 mL) was added to the vial via syringe; the mixturewas stirred for 10 minutes. In a 4 dram vial, 2-chloro-1H-benzimidazole(153 mg, 1.0 mmol), 3-thiophene boronic acid (256 mg, 2.0 mmol) andK₂CO₃ (276 mg, 2.0 mmol) were added with a magnetic stir bar.1,4-dioxane (3 mL) and methanol (2 mL) were added to the vial viasyringe, followed by 1 mL of the 1,4-dioxane/precatalyst solution. Thevial was sealed and stirred outside of the glove box in a pre-calibratedheating block at 80° C. for 15 hours. General Procedure C was followedto yield the product in a 95% yield (192 mg).

In a nitrogen filled glove box, 3d (8.0 mg, 0.0125 mmol) and RuPhos(23.5 mg, 0.025 mmol) were added to a 2 dram vial equipped with amagnetic stir bar. THF (5 mL) was added to the vial via syringe; themixture was stirred for 10 minutes. In a one dram vial, NaO^(t)Bu (115mg, 1.2 mmol) was added with a magnetic stir bar. 2-methoxychlorobenzene (122 μL, 1.0 mmol) and morpholine (104 μL, 1.2 mmol) wereadded via syringe, followed by 1 mL of THF/precatalyst solution. Thevial was sealed and stirred outside of the glove box in a pre-calibratedheating block at 85° C. for 6 hours. General Procedure D was followed toyield the product in a 94% yield (182 mg).

In a nitrogen filled glove box, 3d (15.5 mg, 0.025 mmol) and XPhos (24mg, 0.05 mmol) were added to a 2 dram vial equipped with a magnetic stirbar. THF (5 mL) was added to the vial via syringe; the mixture wasstirred for 10 minutes. In a 1 dram vial, KO^(t)Bu (134 mg, 1.2 mmol)was added with a magnetic stir bar; 3-acetylpyridine (50 μL, 0.5 mmol)and 3-chloropyridine (55 μL, 0.525 mmol) were added by syringe. THF (0.5mL) and methanol (1 mL) were added to the vial via syringe, followed by0.5 mL of the THF/precatalyst solution. The vial was sealed and stirredoutside of the glove box in a pre-calibrated heating block at 60° C. forone hour. General Procedure E was followed to yield the product in a 89%yield (88 mg).

In a nitrogen filled glove box, 3d (15.5 mg, 0.025 mmol) and P(^(t)Bu)₃(10 mg, 0.05 mmol) were added to a 2 dram vial equipped with a magneticstir bar. Toluene (5 mL) was added to the vial via syringe; the mixturewas stirred for 30 minutes. In a 1 dram vial, potassiumisopropyltrifluoroboronate (113 mg, 0.75 mmol) and K₂CO₃ (207 mg, 1.5mmol) were added with a magnetic stir bar; 4-chloroanisole (61 μL, 0.5mmol) was added by syringe. Water (0.5 mL) was added to the vial viasyringe, followed by 1.0 mL of the toluene/precatalyst solution. Thevial was sealed and stirred outside of the glove box in a pre-calibratedheating block at 80° C. for 8 hours. General Procedure F was followed toyield the product in a 97% yield (146 mg).

Example 15 In Situ Catalytic Experiments Comparing(η³-cinnamyl)₂(μ-Cl)₂Pd₂ and 3d as Precatalysts with IPr

The MeOH stock solutions used in FIG. 3 were used.

Preparation of Precatalyst Stock Solutions for 0.5 Mol % Reactions:

(η³-cinnamyl)₂(μ-Cl)₂Pd₂ (12.5 mg, 0.0244 mmol) or 3d (15.0 mg, 0.0244mmol) and IPr (19.0 mg, 0.049 mmol) were added to a 1 mL volumetricflask in a glovebox. THF was added and the solution was diluted to 1 mL.The homogeneous solutions were transferred to 1 dram vials equipped withflea stir bars and the solutions were stirred for one hour at 25° C.After this time, the solutions were transferred to flasks with Kontesvalves. The solutions were used in catalytic experiments without furtherpurification.

Preparation of Precatalyst Stock Solutions for 1.0 Mol % Reactions:

(η³-cinnamyl)₂(μ-Cl)₂Pd₂ (25.0 mg, 0.049 mmol) or 3d (30.0 mg, 0.049mmol) and IPr (38.0 mg, 0.098 mmol) were added to a 1 mL volumetricflask in a glovebox. THF was added and the solution was diluted to 1 mL.The homogeneous solutions were transferred to 1 dram vials equipped withflea stir bars and the solutions were stirred for one hour at 25° C.After this time, the solutions were transferred to flasks with Kontesvalves. The solutions were used in catalytic experiments without furtherpurification.

A comparison of the performation of (η³-cinnamyl)₂(μ-Cl)₂Pd₂ and 3dunder these conditions is given is given in Table 5. The systemgenerated from 3d is a significantly more efficient.

Example 16 One-Pot, In Situ-Catalyst Generation for Heteroaryl CrossCoupling Reaction

In a nitrogen filled glove box, 3d (3.1 mg, 0.005 mmol), XPhos (4.8mg,0.005 mmol), 2-chloro-4,6-dimethoxyprimidine (175 mg, 1.0 mmol),benzofuran-2-boronic acid (243 mg, 1.5 mmol) and K₂CO₃ (276 mg, 2.0mmol) were added to a 4 dram vial with a magnetic stir bar. THF (12mL)and methanol (4 mL) were added to the vial via syringe. The vial wassealed and stirred outside of the glove box in a pre-calibrated heatingblock at 40° C. for one hour. General Procedure B was followed to yieldthe product in a 95% yield (242 mg).

Example 17 Procedures for Suzuki-Miyaura Reactions Using MonomericPrecatalysts of the Invention KO^(t)Bu Conditions:

Reactions were performed under dinitrogen in a 1 dram vial containing aflea stir bar and sealed with a septum cap. To the vial were added 950μL of a MeOH stock solution, containing 0.5263 M aryl chloride, 0.5525 Mboronic acid, 0.5789 M KO^(t)Bu and 0.2632 M naphthalene. The vial wasthen heated using an aluminum block heater set to 25° C. After thermalequilibration, the reaction was initiated via the addition of 50 μL ofthe appropriate precatalyst solution in THF (0.1 M [Pd]). Aliquots(˜50-100 μL) were removed at reaction times indicated. The aliquots werepurified by filtration through pipet filters containing approximately 1cm of silica and eluted with 1-1.2 mL of ethyl acetate directly into GCvials. Conversion was determined by comparison of the GC responses ofproduct and the internal naphthalene standard.

K₂CO₃ Conditions:

Potassium carbonate (0.75 mmol) was transferred on the benchtop into a 1dram vial containing a flea stir bar. The vial was sealed with a septumcap, and placed under dinitrogen (by cycling three times between vacuumand dinitrogen) on a Schlenk line through a needle. To the vial wasadded 950 μL of a MeOH stock solution, containing 0.5263 M arylchloride, 0.5525 M boronic acid and 0.2632 M naphthalene. The vial wasthen heated using an aluminum block heater set to 25° C. After thermalequilibration, the reaction was initiated via the addition of 50 μL ofthe appropriate precatalyst solution in THF (0.1 M [Pd]). Aliquots(˜50-100 μL) were removed at reaction times indicated. The aliquots werepurified by filtration through pipet filters containing approximately 1cm of silica and eluted with 1-1.2 mL of ethyl acetate directly into GCvials. Conversion was determined by comparison of the GC responses ofproduct and the internal naphthalene standard.

Example 18 Representative Procedures for Suzuki-Miyaura Reactions UsingDimeric Precatalysts of the Invention.

In a 1 dram vial equipped with a flea stir bar, 0.05 M [Pd]_(tot) THFsolution (KO^(t)Bu experiments) or 0.1 M [Pd]_(tot) THF solution (K₂CO₃experiments) were prepared by mixing the appropriate Pd(II) precursorwith two equivalents of IPr under an atmosphere of dinitrogen. Thesolution was stirred for one hour at room temperature to allow for thegeneration of the appropriate ligated Pd(II) precatalyst. Thesesolutions were used in catalytic experiments without any furthertreatment as described elsewhere herein.

Example 19 Suzuki-Miyaura reactions using aryl sulfamates

To a one dram vial equipped with a flea stir bar,N,N-dimethyl(1-naphthyl) sulfamate (32.7 mg, 0.13 mmol, 1 eq),4-methoxyphenyl boronic acid (50.3 mg, 0.33 mmol, 2.5 eq), potassiumcarbonate (88 mg, 0.6 mmol, 4 eq), and palladium precatalyst (0.00325mmol, 2.5 mol %) were added under an atmosphere of nitrogen. Toluene (1mL) was added to start the reactions; each vial was stirred for 4 hoursat 25° C. at which time it was opened to air.

Conversion to product was determined using GC analysis.

Example 20 Hiyama-Denmark Reactions Using Aryl Chlorides

In a nitrogen filled glove box, dimethyl-(4-methoxyphenyl)silanol (54μL, 0.3 mmol, 1.5 eq) and sodium hydride (8.5 mg, 0.36 mmol, 1.8 eq)were added to a one dram vial along with toluene (1 mL). This mixturewas allowed to age for 30 minutes. At this time,4-(trifluoromethyl)-chlorobenzene (27 μL, 0.2 mmol, 1 eq) and palladiumprecatalyst (0.002 mmol, 1 mol %) were added in an additional 0.5 mL oftoluene to start the reaction. Each vial was stirred for 18 hours at 70°C. Conversion to product was determined by GC analysis.

Example 21 Hiyama-Denmark Reactions Using Aryl Sulfamates

In a nitrogen filled glove box, dimethyl-(4-methoxyphenyl)silanol (54μL, 0.3 mmol, 1.5 eq) and sodium hydride (8.5 mg, 0.36 mmol, 1.8 eq)were added to a one dram vial along with toluene (1 mL). This mixturewas allowed to age for 30 minutes. At this time,N,N-dimethyl(4-[trifluoromethyl]phenyl)sulfamate (0.13 mmol, 1 eq) andpalladium precatalyst (0.002 mmol, 1 mol %) were added in an additional0.5 mL of toluene to start the reaction. Each vial was stirred for 18hours at 70° C. Conversion to product was determined by GC analysis.

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety. While this invention has been disclosed with referenceto specific embodiments, it is apparent that other embodiments andvariations of this invention may be devised by others skilled in the artwithout departing from the true spirit and scope of the invention. Theappended claims are intended to be construed to include all suchembodiments and equivalent variations.

1. A precatalyst of formula (I), or a salt or solvate thereof:

wherein in (I): each occurrence of M is independently a transitionmetal; each occurrence of X is independently a ligand; each occurrenceof R is independently selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, heteroaryl and substituted heteroaryl; with the provisothat each of the 5-membered rings is substituted with at least oneindependently selected R; Z is CH, CR or N, with the proviso that 0-2 Zgroups are N; or the Z groups at the 5- and 6-positions are null and theZ groups at the 4- and 7-positions are independently R; and, n is 1, 2,3, or
 4. 2. The precatalyst of claim 1, wherein each occurrence of M isindependently selected from the group consisting of Pd, Ni and Pt. 3.The precatalyst of claim 1, wherein at least one applies: the twooccurrences of M in (I) are identical; (ii) the two occurrences of X in(I) are identical; (iii) the two ligands comprising 5-membered rings areidentical. 4-5. (canceled)
 6. The precatalyst of claim 1, wherein eachof the two occurrences of X in (I) is independently a weaklycoordinating ligand.
 7. The precatalyst of claim 1, wherein each of thetwo occurrences of X in (I) is independently selected from the groupconsisting of halide, trifluoromethanesulfonate (triflate), tosylate,mesylate, tetrafluoroborate, tetraphenylborate, hexafluorophosphine,acetate, trifluoroacetate, acetonitrile, tetrahydrofuran,dichloromethane and water. 8-9. (canceled)
 10. The precatalyst of claim1, wherein each of the 5-membered rings is substituted with at least oneR.
 11. The precatalyst of claim 10, wherein each of the 5-membered ringsis substituted with at least one R selected from the group consisting ofmethyl, isopropyl and tert-butyl.
 12. The precatalyst of claim 1,wherein (i) the 1- or 3-position, or (ii) the 2-position, of each of the5-membered rings is substituted with R. 13-14. (canceled)
 15. Aprecatalyst of formula (II), or a salt or solvate thereof:

wherein in (II): M is a transition metal; X is a ligand; each occurrenceof R is independently selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, heteroaryl and substituted heteroaryl; with the provisothat the 5-membered ring is substituted with at least one R; Z is CH, CRor N, with the proviso that 0-2 Z groups are N; or the Z groups at the5- and 6-positions are null and the Z groups at the 4- and 7-positionsare independently R; L is a monodentate or bidentate ligand; and n is 1,2, 3, or
 4. 16. The precatalyst of claim 15, wherein L is a bidentateligand, and wherein (i) X is present and coordinates to M, or (ii) X isabsent and does not coordinate to M.
 17. (canceled)
 18. The precatalystof claim 15, wherein M is selected from the group consisting of Pd, Niand Pt.
 19. (canceled)
 20. The precatalyst of claim 15, wherein X is aweakly coordinating ligand.
 21. The precatalyst of claim 15, wherein Xis selected from the group consisting of halide,trifluoromethanesulfonate (triflate), tosylate, mesylate,tetrafluoroborate, tetraphenylborate, hexafluorophosphine, acetate,trifluoroacetate, acetonitrile, tetrahydrofuran, dichloromethane andwater.
 22. The precatalyst of claim 15, wherein the 5-membered ring issubstituted with at least one R.
 23. The precatalyst of claim 15,wherein the 5-membered ring is substituted with at least one R selectedfrom the group consisting of methyl, isopropyl and tent-butyl.
 24. Theprecatalyst of claim 15, wherein (i) the 1- or 3-position, or (ii) the2-position, of the 5-membered rings is substituted with R. 25-26.(canceled)
 27. The precatalyst of claim 15, wherein L is selected fromthe group consisting of: (i) a ligand selected from the group consistingof 1,3-bis(2,6-diisopropyl phenyl)-1,3-dihydro-2H-imidazol-2-ylidene and1,3-bis(2,6-bis-(diphenylmethyl)-4-methoxyphenyl)imidazol-2-ylidene;(ii) a monodentate phosphine ligand; and (iii) a bidentate phosphineligand.
 28. (canceled)
 29. The precatalyst of claim 15, wherein L is atleast one selected from the group consisting of AmPhos(di-t-butylphosphino-4-dimethylaminobenzene), DavePhos(2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl), ^(tBu)DavePhos(2-Di-tert-butylphosphino-2′-(N,N-dimethylamino)biphenyl), QPhos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene), RuPhos(2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl), Phos(2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl), XPhos(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), ^(tBu)XPhos(2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl), ^(Me4tBu)XPhos(2-Di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl),BrettPhos(2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl),^(tBu)BrettPhos (2-(Di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl), ^(Ad)BrettPhos(2-(Diadamantylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl), Me-DalPhos(2-(Di-1-adamantylphosphino) phenylpiperidine), Mor-DalPhos(Di(1-adamantyl)-2-morpholinophenylphosphine),Di(1-adamantyl)-1-piperidinyl-phenylphosphine, triphenylphosphine,tri(o-tolyl) phosphine, tricyclohexylphosphine andtri(t-butyl)phosphine.
 30. (canceled)
 31. The precatalyst of claim 15,wherein L is selected from the group consisting of1,1′-bis(diphenylphosphino)ferrocene (DPPF),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), 4,6-bis(diphenylphosphanyl)-10H-phenoxazine (NiXantPhos),1,2-bis(diphenylphosphino)ethane (dppe),1,1-bis(diphenylphosphino)methane (dppm),1,3-bis(diphenylphosphino)propane (dppp),1,4-bis(diphenylphosphino)butane (dppb), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), bis[(2-diphenylphosphino) phenyl] ether(DPEPhos), 1,2-bis(dichlorophosphino) ethane, and1,2-bis(dicyclohexylphosphino)-ethane (dcpe).
 32. A method of preparingthe precatalyst of claim 1, the method comprising contacting a mixedalkaline/transition metal or alkaline-earth/transition metal salt withthe ligand

in the presence of a base in an organic solvent to form a reactionmixture.
 33. The method of claim 32, wherein at least one of thefollowing applies: (a) the base comprises sodium carbonate; (b) theorganic solvent comprises methanol; (c) the precatalyst precipitatesfrom the reaction mixture; (d) the mixed salt comprises [E]MX₂, wherein[E] is Na₂, K₂, Ca or Mg; (e) the mixed salt comprises Na₂PdCl₂; themixed alkaline/transition metal salt or a mixedalkaline-earth/transition metal salt is prepared by contacting MX₂ withan alkaline or alkaline-earth salt in solution. 34-38. (canceled)
 39. Amethod of preparing the precatalyst of claim 15, the method comprisingcontacting a catalyst of formula (I), or a salt or solvate thereof, witha ligand L, wherein the catalyst of formula (I) is:

wherein in (I): each occurrence of M is independently a transitionmetal; each occurrence of X is independently a ligand; each occurrenceof R is independently selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, heteroaryl and substituted heteroaryl; with the provisothat each of the 5-membered rings is substituted with at least oneindependently selected R; Z is CH, CR or N, with the proviso that 0-2 Zgroups are N; or the Z groups at the 5- and 6-positions are null and theZ groups at the 4- and 7-positions are independently R; and, n is 1, 2,3, or 4; and wherein L is a monodentate or bidentate ligand. 40.(canceled)
 41. A method of promoting a reaction between a first reagentand a second reagent, the method comprising contacting the first reagentand the second reagent in the presence of at least one selected from thegroup consisting of (a) the precatalyst of formula (I), or a salt orsolvate thereof, and a ligand L wherein the precatalyst of formula (I)is:

wherein in (I): each occurrence of M is independently a transitionmetal; each occurrence of X is independently a ligand; each occurrenceof R is independently selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, heteroaryl and substituted heteroaryl; with the provisothat each of the 5-membered rings is substituted with at least oneindependently selected R; Z is CH, CR or N, with the proviso that 0-2 Zgroups are N; or the Z groups at the 5- and 6-positions are null and theZ groups at the 4- and 7-positions are independently R; and, n is 1, 2,3, or 4; and wherein L is a monodentate or bidentate ligand; and (b) theprecatalyst of claim 15 of formula (II), or a salt or solvate thereof:,

wherein in (II): M is a transition metal; X is a ligand; each occurrenceof R is independently selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, heteroaryl and substituted heteroaryl; with the provisothat the 5-membered ring is substituted with at least one R; Z is CH, CRor N, with the proviso that 0-2 Z groups are N; or the Z groups at the5- and 6-positions are null and the Z groups at the 4- and 7-positionsare independently R; L is a monodentate or bidentate ligand; and n is 1,2, 3, or 4; wherein the first reagent and the second reagent areselected from the group consisting of:. (i) the first reagent is anaromatic or heteroaromatic boronic acid or ester, and the second reagentis an aromatic or heteroaromatic halide, tosylate, triflate, mesylate,sulfamate or carbamate; (ii) the first reagent is an aromatic orheteroaromatic amine, and the second reagent is an aromatic,heteroaromatic or vinylic halide, tosylate, triflate, mesylate,sulfamate or carbamate; (iii) the first reagent is an aromatic orheteroaromatic zinc halide, and the second reagent is an aromatic,heteroaromatic or vinylic halide, tosylate, triflate, mesylate,sulfamate or carbamate; (iv) the first reagent is an aromatic orheteroaromatic magnesium halide, and the second reagent is an aromatic,heteroaromatic or vinylic halide, tosylate, triflate, mesylate,sulfamate or carbamate; (v) the first reagent is an aromatic orheteroaromatic tin halide, and the second reagent is an aromatic,heteroaromatic or vinylic halide, tosylate, triflate, mesylate,sulfamate or carbamate; (vi) the first reagent is a ketone, aldehyde,imine, amide or ester, and the second reagent is an aromatic,heteroaromatic or vinylic halide, tosylate, triflate, mesylate,sulfamate or carbamate; (vii) the first reagent is an alcohol or thiol,and the second reagent is an aromatic, heteroaromatic or vinylic halide,tosylate, triflate, mesylate, sulfamate or carbamate; (viii)the firstreagent is an aromatic or heteroaromatic silanol, siloxane or silane,and the second reagent is an aromatic, heteroaromatic or vinylic halide,tosylate, triflate, mesylate, sulfamate or carbamate.
 42. (canceled) 43.A method of promoting anaerobic oxidation of a primary or secondaryalcohol, the method comprising contacting the primary or secondaryalcohol with at least one selected from the group consisting of: (a) aprecatalyst of formula (I), or a salt or solvate thereof, and a ligandL, wherein the precatalyst of formula (I) is:

wherein in (I): each occurrence of M is independently a transitionmetal; each occurrence of X is independently a ligand; each occurrenceof R is independently selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, heteroaryl and substituted heteroaryl; with the provisothat each of the 5-membered rings is substituted with at least oneindependently selected R; Z is CH, CR or N, with the proviso that 0-2 Zgroups are N; or the Z groups at the 5- and 6-positions are null and theZ groups at the 4- and 7-positions are independently R; and, n is 1, 2,3, or 4; and wherein L is L is a monodentate or bidentate ligand; and(b) a precatalyst of formula (II), or a salt or solvate thereof:

wherein in (II): M is a transition metal; X is a ligand; each occurrenceof R is independently selected from the group consisting of alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, heteroaryl and substituted heteroaryl; with the provisothat the 5-membered ring is substituted with at least one R; Z is CH, CRor N, with the proviso that 0-2 Z groups are N; or the Z groups at the5- and 6-positions are null and the Z groups at the 4- and 7-positionsare independently R; L is a monodentate or bidentate ligand; and n is 1,2, 3, or 4.